FR2583757A1 - 3-SUBSTITUTED PROPENYLAMINOTHIAZOLYLCEPHALOSPORANIC ACIDS AND THEIR ESTERS - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION IS A COMPOUND OF THE FORMULA: (CF DRAWING IN BOPI) IN WHICH: R REPRESENTS A HYDROGEN ATOM OR A CLASSIC PROTECTIVE AMINO GROUP; R REPRESENTS A HYDROGEN ATOM, A STRAIGHT OR BRANCHED ALKYL CHAIN CONTAINING 1 TO 4ATOMS OF CARBON, A RADICAL ALKENYL OR ALKYNYL CONTAINING 2 TO 4ATOMS OF CARBON, CYCLO-ALKYL CONTAINING FROM 3 TO 6ATOMS OF CARBON, A RADICAL ALKENYL OR ALKYNYL CONTAINING FROM 2 TO 4ATOMS OF CARBON, CYCLO-ALKYL CONTAINING FROM 3 TO 6 KYLKYLFERMALKYL, RENALKYLKYL RENALBYLFERMAL WITH 6 ELEMENTS IN THE CYCLE AND 4 TO 10ATOMS OF CARBON OR ALKANOYL CONTAINING FROM 2 TO 4ATOMS OF CARBON; R REPRESENTS AN ATOM OF HYDROGEN, A LOWER RADICAL ALKYL CONTAINING 1 TO 3ATOMS OF CARBON, LOWER ALKOXY CONTAINING 1 TO 3ATOMS OF CARBON, LOWER ALKANOYLOXY CONTAINING FROM 2 TO 3ATOMS OF CARBON; AND R REPRESENTS A HYDROGEN ATOM OR A PHYSIOLOGICALLY HYDROLYSABLE ESTER GROUP. IT RELATES TO 3-SUBSTITUTE PROPENYLAMINOTHIAZOLYLCEPHALOSPORANIC ACIDS AND THEIR ESTERS.

Description

2583 7 57

  3-SUBSTITUTED PROPENYLAMINOTHIAZOLYLCEPHALOSPORANIC ACIDS AND

THEIR ESTERS

  The subject of the present invention is cephalosporanic acids and their esters, of general formula:

N C CONH

H 2 / CH = CHCH R 3

2 N to oR2 o

COOR 4

in which:

  R2 represents a hydrogen atom, a lower alkyl radical,

  lower nyl, lower alkynyl, cyclo-lower alkyl or acyl; R3 represents a hydrogen atom, a lower alkyl radical, lower alkoxy, lower alkanoyloxy; and R4 represents a hydrogen atom, a pivaloyloxymethyl radical,

  acetoxymethyl, 1-acetoxyethyl, 5-methyl-2-oxo-1,3-dioxolene-4-yl

  methyl, 1- (ethoxycarbonyloxy) ethyl or 4-glycyloxybenzoyloxymethyl.

  These compounds, especially esters, are useful as broad-spectrum antibiotics in the treatment and prevention of infectious diseases of

  mammals and for other purposes known in the state of the art.

  (A) Published European Patent Application No. 30,630 discloses a large number of 7-acylamino-3-vinylcephalosporanic acid derivatives including, inter alia, those of the formula: ## STR2 ##

2O--

Coot

  in which R can, inter alia, represent a lower alkyl radical

  lower alkenyl, lower alkynyl or carboxy-lower alkyl.

  These compounds are prepared inter alia by reaction of the 3-halogenated

  corresponding methyl with triarylphosphine, followed by base treatment and reaction with formaldehyde. In each case, the final substituent in position 3 is the vinyl group. There

  no description or suggestion of a propenyl or propenyl radical

  substitute in position 3. There is also no description of

  or suggestion of a pre-drug ester for oral use based on the 4-carboxylic acid moiety. This compound in which R represents -CH2CO2H has been designated in the literature under the name

of FK-027 and cefvixim.

  (B) British Patent No. 1,399,086 contains a generic description

  which encompasses a whole series of cephalosporins of formula:

B

R-C -CONH-r <N a a

OR ó

  COOR wherein R represents a hydrogen atom or an organic group;

  Ra represents a monovalent organic etherifying group connected to the oxy-

  gene by a carbon atom, B represents> S or> S> 0; and

P represents an organic group.

  In one embodiment, P may among others represent a vinyl group of formula: R 3

-CH = C <

R4

  in which: R 3 and R 4 may independently represent a hydrogen atom, a nitrile radical, a lower alkoxycarbonyl radical or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, substituted or unsubstituted

substituted.

  However, the 2-amino-thiazol-4-yl group is not identified as a

  substituent R possible and there is no description nor suggestion of a

  ester as a pre-drug for oral use containing its 4 carboxylic acid.

  U.S. Patent 3,971,778 and its Divisions Nos. 4,024,133, 4,024,137, 4,064,346, 4,033,950, 4,079,178, 4,091,209,

  4,092,477 and 4,093,803 give similar descriptions.

  (C) U.S. Patent No. 4,307,233 discloses, inter alia, 3-vinylcephalosporin derivatives of the formula:

N 3

H2N N S OR H = CHN

COOH R

  wherein: R5 may inter alia represent an alkyl, vinyl, cyanomethyl radical or a protecting group such as 2-methoxyprop-2-yl; and R3 and R4 represent alkyl groups (optionally substituted with hydroxy, alkoxy, amino, alkylamino or dialkylamino) or phenyl groups; or R3 and R4, taken together with the nitrogen atom to which they are attached, can form a 5- or 6-membered saturated heterocyclic ring, optionally containing another heteroatom selected from

  Ni, O and S, and optionally substituted by an alkyl group.

  The compounds are useful as intermediates in the preparation of

  3-thiovinylcephalosporin derivatives. There is no description nor of

  suggestion of a substituted or unsubstituted propenyl radical for the

  substitute in position 3 and there is no description or

  suggestion containing a pre-drug ester of 4-carboxylic acid for oral use. Published British Patent Application No. 2,051,062 concurs

  with that and she gives a similar description.

  (D) Published European Patent Application No. 53,537 describes, inter alia, 3-vinylcephalosporin derivatives of the formula:

N CONH R

N H2N S o COOR N CH = CH-N CR4

COOR 2

R5 R

4 2583757

  wherein: R5 and Rb are the same or different and represent hydrogen or an alkyl radical, or taken together they form an alkylene group containing 2 to 3 carbon atoms; Rc represents an acidic protecting group; R2 represents an acidic protecting group, such as, for example, an ester; R3 and R4 are the same and different and represent a hydrogen atom, an alkyl radical (optionally substituted with a hydroxy, alkoxy, amino, alkylamino or dialkylamino group) or phenyl groups; or R3 and R4, taken together with the nitrogen atom to which they are attached, can form a saturated heterocyclic ring

  containing 5 to 6 elements, possibly containing another hetero-

  atom selected from N, O and S, and optionally substituted with

alkyl group.

  The compounds are useful as intermediates in the preparation of

  3-thiovinylcephalosporin derivatives. There is no description nor of

  suggestion of a substituted or unsubstituted propenyl group as a substitute

  killing in position 3 and a 4-carboxylic acid ester for use

orally.

  (E) U.S. Patent 4,307,116 discloses 3-thiovinyl-

cephalosporins of the formula:

N5, - CONH-

1, iii

H2NJY1 - "'CRH-CH-SR

COOH in which:

  R represents a hydrogen atom, an alkyl, vinyl or cyano-

  methyl; and R can inter alia represent one of a whole series of heterocyclic rings.

  There is no description or suggestion of a substituted propenyl radical

  killed or unsubstituted as a substituent in position 3 and there is no

  no description or suggestion of any of its esters for use

orally.

2583757

  (F) The published European Patent Application No. 53 074 generically describes a series of 3-vinylcephalosporin derivatives of the formula: ## STR2 ## wherein: ## STR1 ## wherein: (in one or more embodiments) may represent:

N CCO-

NOT

H2N 'S NOR5

  in which: R5 may inter alia represent a hydrogen atom, an alkyl, vinyl, cyanomethyl radical, a protective oxime group such as for example trityl, etc., or a group of formula:

COORC

  In which: Ra and Rb are identical or different and can represent a hydrogen atom, an alkyl radical or, taken together, an alkylene radical containing from 2 to 3 carbon atoms; and R5c represents a hydrogen atom or a protective acid radical; R2a represents a hydrogen atom or a protective acid radical, such as, for example, methoxymethyl; R (in one or more embodiments) may represent a methyl group substituted with a 5- to 6-membered aromatic heterocyclic ring containing a single heteroatom, such as, for example, 2- or 3-pyridyl, 2- or 3-thienyl or 2 - or 3-furyl; and R3 represents a group of formula:

R4S020-

in which:

  R4 may represent an alkyl, trihalomethyl or optionally

a substituted phenyl.

6 2583757

  These compounds are said to be intermediates in the preparation of compounds in which the 3-position substituent is a group of the formula: R

-CH = C-SR

  and exhibit antibacterial activity. Although this patent contemplates the possibility that R may be a methyl group substituted by a nitrogen atom containing heterocyclic ring, both in the intermediates and in the final product (thereby giving a substituted heterocyclic propenyl radical), the reference gives as a RO example in the intermediates and in the final product only in the form of methyl and further, in both the intermediates and the final product, the propenyl group must contain a second substituent (respectively -03SR4

  or -SR). There is no description or suggestion of any of these esters

for oral use.

  (G) The published European Patent Application No. 53,538 discloses, inter alia, 3-vinylcephalosporin intermediates of the formula: ## STR2 ##

OR-N OR CH-CH-R3

  NOO wherein: n is 0 or 1; R5 represents hydrogen, alkyl, vinyl, cyanomethyl or a protective oxime group; and

  R3 represents a halogen atom.

  The subject of the present invention is new cephalosphate derivatives

  which are potent antibacterial agents and some of which can be used orally. More particularly, it relates to compounds of formula ## STR2 ## in which: ## STR1 ##

  R1 represents a hydrogen atom or a classically protective amino group;

  if that; R2 represents a hydrogen atom, a straight or branched chain alkyl radical containing from 1 to 4 carbon atoms, an alkenyl or alkynyl radical containing from 2 to 4 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, cycloalkylalkyl enclosing

  3 to 6 ring members and 4 to 10 carbon atoms, or acyl

mantle of 2 to 4 carbon atoms;

  R3 represents a hydrogen atom, a lower alkyl radical

  1 to 3 carbon atoms, a lower alkoxy radical

  mantle of 2 to 3 carbon atoms, a lower alkanoyloxy radical containing from 2 to 3 carbon atoms; and R4 represents a hydrogen atom or physiologically hydrolysable groups, such as, for example, acetoxymethyl groups,

  1-acetoxyethyl, pivaloyloxymethyl, 5-methyl-2-oxo-1,3-dioxolene

  4-ylmethyl, 1- (ethoxycarbonyloxy) ethyl, or 4-glycyloxybenzoyloxy

  methyl. Also within the scope of the invention are pharmaceutically acceptable acid addition salts, metal salts (when R4 is H) and solvates (including hydrates) of the compounds of formula I which may exist in various forms. tautomers, also

  including, for example, the 2-iminothiazolin-4-yl form of the 2-amino radical

  thiazol-4-yl. In another aspect, the present invention relates to a process for the preparation of the compounds of formula I. As shown by the structural formula, the compounds of formula I

  have the configuration "syn" or T "Z" with respect to the alkoxyimino group.

  The compounds being geometric isomers, some "anti" isomers

  may also be present. The present invention comprises

  ss of formula I containing at least 90% of the "syn" isomer. Preferably, the compounds of formula I are "syn" isomers which are essentially

  free from the corresponding isomers "anti".

  In addition to the possible geometrical isomers, with regard to the alkoxy-

  imino, the compounds of formula I (and intermediates VIII, XII, XIII and XIV) also form geometric isomers (cis and trans, or Z and E) around the double bond of the propenyl group at the 3-position. The cis isomers ( "Z") and trans ("E") of these compounds are both specifically

  included within the scope of the present invention.

  The pharmaceutically acceptable acid addition salts of

  formula I are those in which the anion does not contribute significantly

  ficative to salt toxicity and are compatible with usual pharmaceutical vehicles and suitable for oral or parenteral administration. The pharmaceutically acceptable acid addition salts include the salts of formula I with the mineral acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, with organic carboxylic acids or organic sulphonic acids such as, for example, acetic acid, citric acid, maleic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid and other acids known and used in the field of penicillin and cephalosporin. The preparation of these salts is carried out by conventional techniques involving the reaction of formula I with the acid in a quantity

substantially equivalent.

  These substances of formula I in which R4 represents an atom

  of hydrogen also form salts of metals and pharmaceutical amines.

  in which the cation does not contribute significantly to the toxicity or biological activity of the salt. These salts

  are also part of the present invention. The metal salts

  include sodium, potassium, barium, zinc and aluminum salts.

  minium. The sodium or potassium salts are those which are preferred. The amine salts prepared from the amines used for example with benzyl penicillin which are capable of forming stable salts with the acidic carboxylic group, include trialkylamines such as

  triethylamine, procaine, dibenzylamine, N-benzyl-O-

  phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, dehydro-

  abiethylamine, N-ethylpiperidine, benzylamine and dicyclohexyl-

amine.

  The physiologically hydrolysable esters serve as pre-drugs by hydrolyzing in the body to give the antibiotic per se. They are preferably administered orally since, in many cases,

  hydrolysis occurs mainly under the influence of digestive enzymes.

  tives. Parenteral administration can be used when the ester itself is active or in cases where hydrolysis occurs in the blood. Suitable esters are acetoxymethyl, pivaloyloxymethyl,

  1-acetoxyethyl, 1-pivaloyloxyethyl, 3-phthalidyl, p-glycyloxy-

9 2583757

  benzoyloxymethyl, 5-methyl-1,3-dioxacyclopent-4-en-2-one-4-ylmethyl

  and others known in the field of penicillin and cephalosporin

  rine. The most preferred esters are 1-acetoxyethyl and pivaloyloxymethyl. The compounds of formula I may be included in the formulations for oral or parenteral use in conventional manner using known pharmaceutical carriers and excipients and may be in unit dosage form, or in multiple dose packages. The composition can be in the form of tablets, capsules, solutions, suspensions or emulsions. These compounds can also be

  formulas in the form of suppositories using suppository bases.

  conventional materials such as cocoa butter or other

  fat. The compounds may, if desired, be administered in combination with

  with other antibiotics, including cephalosporins,

  penicillins and aminoglycosides.

  When carried out in unit dosage form, the compositions preferably contain from about 50 to about 1500 mg of active ingredient of formula I. The dosage of the compounds of formula I depends on such factors as weight and weight. Age of the patient, as well as the particular nature and

  the severity of the disease, and it is at the discretion of the physician.

  However, the dosage for the treatment of adult man is usually

  from about 500 to about 5000 mg / d depending on the frequency and route of administration. When administered intramuscularly or intravenously to an adult patient, a total dose of about 750 to about 3000 mg / day, in divided doses,

will normally be sufficient.

  In the compounds of formula I, hydrogen is particularly

  preferred for R 1, hydrogen, acetyl or methyl for R 2 and

  loyloxymethyl or 1-acetoxyethyl for R4. The compounds that we prefer

  especially according to the invention are listed below and the experimental details are

  of their preparation and characterization are given next.

  Those not represented by a specific example are getting ready

  easily by similar procedures.

  1) 78 {(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] acid

  -r (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  2) 1-Acetoxyethyl-7 {(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -34 (Z) -prop-1-ene-1-yl] -3-ciphem-4-carboxylate;

  3) pivaloyloxymethyl-7e - (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamidol-3 {(Z) -prop-1-ane-1-yl] -3-cephem-4-carboxylate;

  4) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3- [(E) -) acid

  prop-1-en-1-yl] -3-cephem-4-carboxylic acid; ) 1-Acetoxyethyl-7e-E (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -acetamido] -3- (E) -prop-1-en-1-yl] 3-cephem -4-carboxylate; 6) pivaloyloxymethyl-7- [E (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -acetamido] -3 - [(E) -prop-1-en-1-yl] -3 -cêphem-4carboxylate;

  7) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z)] acid

  but-1-en-1-yl] -3-cephem-4-carboxylic acid;

  8) acetoxymethyl-70- [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamidol-3-E (Z) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  9) 1-Acetoxyethyl-70 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3-E (Z) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  ) pivaloyloxymethyl-70- (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3 - [(Z) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  11) 4-glycyloxybenzoyloxymethyl-70 - [(Z) -2- (2-aminothiazol-4-yl) -2-

  (methoxyimino) acetamido] -3 - [(Z) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  12) 70-E [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido) -3-

  (E) -but-1-en-1-yl] -3-cephem-4-carboxylic acid;

  13) acetoxymethyl-70- [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3- (3) -but-1-ene-1-yl] -3-cephem-4-carboxylate;

  14) 1-Acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxylmino) -

  acetamido -3 - [(E) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  ) pivaloyloxymethyl-70 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3 - [(E) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  16) 4-glycyloxybenzoyloxymethyl-70 - [(Z) -2- (2-aminothiazol-4-yl) -2-

  (methoxyimino) acetamido] -3 - [(E) -but-1-en-1-yl] -3-cephem-4-carboxylate;

  17) 70- [(Z) -2- (2-Aminothiazol-4-yl) -2- (methoxyimino) acetamido] -1-3- acid

  (Z) -pent-1-en-1-yl] -3-cephem-4-carboxylic acid;

  18) 1-Acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3 - [(Z) -pent-1-ene-1-yl] -3-cephem-4-carboxylate;

  19) pivaloyloxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxylmino) -

  acetamido] -3 - [(Z) -pent-1-ene-1-yl] -3-cephem-4-carboxylate;

  ) 78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamidol-3- acid

  (E) -pent-1-en-1-yl) -3-cephem-4-carboxylic acid;

  21) 1-acetoxyethyl-70 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3-E (E) -pent-1-en-1-yl] -3-cephem-4-carboxylate;

  22) pivaloyloxymethyl-7-E (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3 - [(E) -pent-1-en-1-yl] -3-cephem-4-carboxylate;

  23) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-

  [(Z) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  24) 1-Acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3 - [(Z) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate; 25) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  26) 78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-

  [(E) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid,

  27) 1-Acetoxyethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3 - [(E) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  28) pivaloyloxymethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3 - [(E) -3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  29) 7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3-

  [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  30) 1-Acetoxyethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -prop-l-ene-l-yl] -3-cephem-4-carboxylate;

  31) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  32) acetoxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  33) 78 - [(Z) -2- (2-Aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3-

  E (E) -prop-l-ene-l-yl] -3-cephem-4-carboxylic acid;

  34) acetoxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(E) -prop-l-ene-l-yl) -3-cephem-4-carboxylate;

  35) 1-Acetoxyethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(E) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  36) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(E) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  37) 78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3-

  E (Z) -3-acêtoxyprop-1-ene-1-yl] -3-cephem-4-carboxylic acid;

  38) acetoxymethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  39) 1-Acetoxyethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -3-acêtoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  40) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  41) 78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3-

  E (E) -3-acêtoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  42) acetoxymethyl-78-E (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3-E (E) -3-acêtoxyprop-1-ene-1-yl] -3-cephem-4-carboxylate;

* 43) 1-Acetoxyethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -

  acetamido] -3 - [(E) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate; 44) pivaloyloxymethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3-E [(E) -3-acetoxyprop-1-en-1-yl) ] -3-cephem-4-carboxylate;

  ) 78-E [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-

  E (Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  46) acetoxymethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3-E [(Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  47) 1-Acetoxyethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3 - [(Z) -3-acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  48) pivaloyloxymethyl-7e-E (Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3-E [(Z) -3-acétoxyprop-1-ene-1-yl] -3-cephem-4-carboxylate;

  49) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-

  [(E) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  acetoxymethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino)]

  acetamido] -3 - [(E) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  51) 1-Acetoxyethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3-E (E) -3-acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  52) pivaloyloxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -

  acetamido] -3-E (E) -3-acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  53) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3-

  E (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  54) acetoxymethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-E (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  ) 1-Acetoxyethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-E (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  56) pivaloyloxymethyl-78-E (Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3- (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  57) 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl-7-E [(Z) -2- (2-aminothiazol-4-)

  yl) -2- (acetoxyimino) acetamido] -3-E [(Z) -prop-1-en-1-yl] -3-cephem-4-

carboxylate;

  58) 7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3-

  [(E) -prop-l-ene-l-yl] -3-cephem-4-carboxylic acid;

  59) acetoxymethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-E (E) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  ) 1-acetoxyethyl-7-E [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-E (E) -prop-1-en-1-yl] -3-cephem-4-carboxylate; -12

13 2583757

  61) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido3-3 - [(E) -prop-1-en-l-yl] -3-cephem-4-carboxylate;

  62) 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl-7e - [(Z) -2- (2-aminothiazol-4-)

  yl) -2- (acetoxyimino) acetamido] -3-f (E) -prop-1-en-1-yi'1-3-c-PHEM-4-

carboxylate;

  63) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acAtamido] -3-

  (Z) -3-acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  64) acetoxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-r (Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  65) 1-Acetoxyethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (actoxyimino) -

  acétamidol-3 - [(Z) -3-acétoxyprop-1-ene-1-yl] -3-cephem-4-carboxylate;

  66) pivaloyloxymethyl-78-r (Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3 - [(Z) -3-acêtoxyprop-1-ene-1-yl1-3-cephem-4-carboxylate;

  67) 5-methyl-2-oxo-1,3-dioxolene-1-4-ylmethyl-7e-r (Z) -2- (2-aminothiazol)

  4-yl) -2- (acetoxyimino) acetamido] -3-r (Z) -3-acêtoxyprop-1-en-1-yl] -3-

cephem-4-carboxylate;

  68) 7-E (Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetoamido acid] -3-

  [(E) -3-acêtoxyprop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  69) 7-acetoxymethyl - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamidol-3-r (E) -3-acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  1-Acetoxytethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido-3-r (E) -3-acétoxyprop-l-ene-l-yl] -3-cephem-4-carboxylate;

  71) pivaloyloxymethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) -

  acetamido] -3-r (E) -3-acêtoxyprop-1-en-1-yl] -3-cephem-4-carboxylate;

  72) 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl-7-r (Z) -2- (2-aminothiazol)

  4-yl) -2- (acetoxyimino) acetamido-3 - [(E) -3-acétoxyprop-1-ene-1-yl] -3-

cephem-4-carboxylate; 73) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (isopropyloxyimino) ac-tamido] acid

  3-r (Z) -prop-l-ene-l-yl] -3-cephem-4-carboxylic acid;

  74) 1-Acetoxyethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (isopropyloxyimino) -

  acetamido] -3-E (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  ) pivaloyloxymethyl-7 $ - [(Z) -2- (2-aminothiazol-4-yl) -2- (isopropyloxy)

  imino) acetamido-3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  76) 7 - [(Z) -2- (2-Aminothiazol-4-yl) -2- (allyloxyimino) acetamido] -3-

  [(Z) -prop-1-en-1-YLJ-3-cephem-4-carboxylic acid;

  77) 1-acetoxyethyl-78-E (Z) -2- (2-aminothiazol-4-yl) -2- (allyloxyimino) -

  acêtamido'-3-r (Z) -prop-1-ene-1-yl] -3-cephem-4-carboxylate;

  78) pivaloyloxymethyl-78r (Z) -2- (2-aminothiazol-4-yl) -2- (allyloxyimino) -

  acetamido] -3-r (Z) -prop-l-ene-l-yl1-3-c6phem-4-carboxylate;

14 2583757

  79) 7- (Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3-

  C (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  ) 1-Acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino)]

  acetamido] -3- (Z) -prop-1-alne-1-yl] -3-cephem-4-carboxylate; 81) pivaloyloxymethyl-7e - [(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3-E (Z) -prop-1-en-1-yl] -3 -cèphem-4-carboxylate;

  82) 7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (cyclopropylmethoxyimino) acid -

  acetamido] -3-r (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  83) 1-Acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (cyclopropylmethoxy)

  imino) acètamidol-3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  84) pivaloyloxymethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (cyclopropyl)

  methoxyimino) acetamido] -3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  ) 7-E (Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxyimino) acetamido acid]

  3-r (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylic acid;

  86) 1-acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxyimino) -

  acetamido-3-r (Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate;

  87) pivaloyloxymethyl-7-E (Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxy)

  imino) acetamidol-3 - [(Z) -prop-1-not-1-yl-3-cephem-4-carboxylate;

  88) (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl-7 - [(Z) -2- (2-aminothiazol)

  4-yl) -2- (hydroxyimino) acetamido] -3-E (Z) -prop-1-en-1-yl] -3-cephem-4-car-

boxylate;

  89) 1- (Ethoxycarbonyloxy) ethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxy);

  imino) acetamido] -3 - [(Z) -prop-1-en-1-yl-3-cephem-4-carboxylate.

  The in vitro anti-bacterial activity of the related cephalosporanic acids of formula I is shown in Table 1 in terms of the geometric mean minimum inhibitory concentrations (MIC's) which are determined by a method of serial double dilution of Mueller agaragar. -Hinton vis-à-vis 25 strains of organisms to be treated in six groups.

  Table 2 shows the blood levels in the mouse of

  ester drugs of formula I which are determined after administration

orally.

  Table 3 shows the in vitro activity of the pre-drug esters of formula I with respect to S. aureus Smith, E. coli Juhl, Pr. Mirabilis A9900,

  Pr. Vulgaris A9436 and Ser. Marcescens A20019.

  Table 4 shows the urinary recovery of various esters in

the mouse.

TABLE 1

  In vitro activity of acidic cephalosporins

N -C- (

2 I S ")

  2J, .N Ia Geometric Mean of MIC (mcg / ml) Compose n GpIa GpIb GnIa GnIb GnII (BMY No) * R2 R3 (5 *) (5) (5) (5) (5)

29 (28232)

37 (28266)

53 (28270)

1 (28098)

4 (28252)

7 (28154)

12 (28204)

17 (28215)

(28217)

(28248)

49 (28280)

23 (28157)

79 (28235)

73 (28233)

76 (28234)

(28237)

82 (28236)

Cefadroxil Cefaclor Cefvixim1)

(FK-027)

Z H Z H Z Ac

Z CH3

E CH3

Z CH3

E CH3

Z CH3

E CH3

Z CH3

E CH3

Z CH3

Z CH2CH3

Z CH (CH3) 2

Z CH2CH = CH2

Z CH2CECH

Z CH2- <

Gp-Ia: Gp-Ib: Gn-Ia:

  S. aureus susceptible to penicillin (PC).

S. aureus resistant to PC.

  E. Coli (2 strains), K. Pneumoniae (1) and

  sensitive to cephalothin (CET).

  P. mirabilis (2) H OAc H H H CH 3 CH 3

CH2CH3

CH2CH3

  OAc OAc OCH3 HHHHH 0,20 0,17 0,17 1,8 2,4 1,8 1,8 1,1 1,2 1,2 0,53 2, 1 2,1 1,6 1,4 1 , 4 0.8 1.4 0.7 4.7 0.40 0.40 0.40 3.6 3.6 3.1 4.1 1.6 2.4 1.6 1.6 2.4 3.1 2.7 1.8 1.6 1.6 3.6 4.7 12.5 0.066 0.025 0.057 0.1 0.3 0, 30 0.69 0.53 0.46 0.05 0.025 0 , 0.30 0.53 0.30 0.23 0.70 8.3 0.92 0.016 0.35 0.1 0.26 0.52 0.91 0.80 1.8 1.2 0, 91 0.15 0.087 0.35 0.91 1.2 1.0 0, 91 1.2 3.1 6.3 3.1 3.6 6.3 8.4 6.3 7.2 6.2 0.91 0.60, 7.3 7.3 7.3 7.3 14.0 8.3> 100> 100 3.2

16 2583757

  Gn-Ib: E. coli (3) and K. Pneumoniae (2) resistant to CET.

  Gn-II: M. morganii (1); E. cloacae (2) and S. marcescens (2).

1) COf 1 It

1 2) N C CN R> CE-CE2

COOH

TABLE 2

  Levels of pre-drug esters in the blood of S II2NJ mice; * .S) \ 42 CCOOR iCIi COOR4 lb 100 mg / kg po 20 mg / kg po

C T1 / 2 AUC C T1 / 2 AUC

  Compound 2 3 max max (BY NoR) R R * (mcg / ml) (h) (mcg.h / ml) (mcg / ml) (h) (mcg.h / m1)

  (28271) H H AX3) Z 36 1.3 61 9.9 1.0 16

  39 (28277) H OAc Z AX (28258) Ac H AX Z 27 0.8 40 7.6 0.8 9.4

  3 (28099) CH3H PV) Z 33 2.2 76 6.9 2.4 18

  2 (28191) CH3 H AX Z 50 2.3 118 21 1.9 37

(28255) CH3 H AX E

  (28155) CH3 CH PV Z 21 3.0 51 6.7 4.0 14

CH C 3 A2)

  8 (28225) CH3 CH3 AMH z 7.4 1.7 15 CH3

  9 (28170) CH3 CH3 AX Z 43 1.5 58 5.0 0.80 7.1

C3 C3 GB4)

  11 (28231) CH3 CH3 GBM4) Z 5.4 2.30 13

C3 C3

  14 (28205) CH3 CH3 AX E 55 7.0 698 12 13 239

  18 (28216) CH CH 2CH3 AX Z 46 2.5 98 9.1 1.9 22

  (28158) CH3 OCH3 PV Z 15 2.3 27 3.3 1.7 6.1

C3 OC3

  24 (28171) CH 0CH3 AX Z 15 1.1 21 4.3 1.3 6.2

  Cefaclor 26 1,2 35 8,5 0,91 8,9 Cefvixtm 28 1,6 75 10 1,5 25 Cefadroxil 57 1,6 69 12 1,4 16

1) PV = -CH20COC (CH3) 3

2) AM = -CH2OCOCH3

3) AX - -CH (CH) OCOCH3

4) CBM - -CH20CO- -OCOCH2NH2

TABLE 3

  In vivo activity of pre-drug esters in PD50 mice (mg / kg, po)

  Compound No. S. aureus E. coli P. mirabi- P. vulga- S. marces-

  (BMY No) Smith Juhl Lily A9900 ris A9436 Cens A20019

(28258) 1.8 0.36

3 (28099) 6.3 4.5

2 (28191) 8.5 1.6

(28155) 7.7 3.4 3.4 0.55 2.6

8 (28225) 11

9 (28170) 6.3 1.7 2.7 <0.39 3.6

11 (28231)> 25

14 (28205) 11

(28158) 8.1

24 (28171) 22.5

  Cefaclor 0.35 0.63 3.0 3.1> 25 Cefvixim> 25 1.6 1.2 0.68 1.1

Cefadroxil 0.4 13 - - -

18 25S83757

TABLE 4

  Urinary recovery of oral pre-drug esters in mice Dose% recovery Compound (mg / kg, po) 0-2 hr 24 hr 4-6 hr 6-24 hr Total BMY-28170a 100 17 6.3 2 , 2 3.5 29 (lot 2)

13 4.0 1.1 1.6 19

FK-027 100 2.9 9.1 6.9 6.5 25

(BB-S 1086 lot 2)

2.8 4.1 3.2 2.9 13

  Standard test a: BMY-28154 b: cefuroxime

  According to another aspect, the subject of the present invention is

  The preferred procedures are shown below in Reaction Schemes 1 and 2. In these reaction schemes, the abbreviation Ph represents the phenyl group. Thus, the radical CH (Ph) 2 represents the benzhydryl group or

  diphenylmethyl, which is a preferred carboxylic protecting group. The abbreviated

  Tr is the trityl or triphenylmethyl group which is a preferred amino protecting group. R2a represents a conventional protecting group used in cephalosporin chemistry with respect to hydroxy groups

  and it includes trityl, chloroacetyl, formyl, trichloro

  ethoxycarbonyl, tert-butoxycarbonyl, carbobenzyloxy, etc. The definition of R2a also includes the same groups as those included in the

  definition of R2, except hydrogen.

  Reaction Scheme 1 shows that the side-chain acid at the desired position 7 is introduced in an advanced stage. Then the group at position 3 is converted into a substituted propenyl radical. On the other hand, in Scheme 2, the 7-amino group of the starting compound 2 is protected as a Schiff's base during the majority of the reaction step and

  the desired side chain acid 7 is added later in the synthesis.

  Deblocking both VIII and XIV affords the cognate acids which are converted to pre-drug esters Ib by conventional procedures. Reaction Scheme 1 shows two possible ways of passing from compound IV to compound VI. One of these means is the direct route of the reaction of the chlorinated derivative IV with triphenylphosphine, which gives the phosphonium and the other means is that the chlorinated derivative is converted into iodo compound V, more active, and then one makes react this one with the

  triphenylphosphine, which gives phosphonium VI. There is no difference

  significant difference in their returns.

  Reaction Scheme 2 shows two possible ways to pass from compound XIII to compound Ia. One of these means is the acylation of XIII with 2-aminothiazolyl acid XX in compound XIV which is followed by a

  deblocking to compound Ia. The other way is acylation by a thiazo-

  lyl acid III containing an amino group protected in 2-N (for example Ntritylamino), which gives the compound VIII which is released to the

compound Ia.

  In reaction schemes i and 2, the benzhydryl group is

  represented as the preferred protective carboxylic group.

  Experts will appreciate that you can also use other

  protective carboxylic groups well known in the state of the art.

  Acylation acid III may be used in the form of a derivative such as its acid halide, an activated ester, a mixed acid anhydride,

  etc., all of which are well known in the state of the art. Acylate acid

  III may also have its amino group protected by any of the conventional amino protecting groups, for example N-trityl, N-formyl,

  N-tertiobutoxycarbonyl or the like.

  The base used to transform the phosphonium halide (VI or X) to give the phosphorylide (VII or XI) may be NaOH, Na2CO3, an IRA-410 resin (OH), an IRA resin (C03-) or the like, or one of their

  mixed. The reaction of ylide VII (or XI) with acetaldehyde or acetaldehyde

  Substituted taldehyde will lead to the 3-propenyl derivative VIII (or XII).

  It was found that compound XII from compound XI (Scheme 2) typically had a Z / E ratio of about 3-5 / 1 for the 3- (1-propenyl) configuration, while compound VIII from VII ( Scheme 1) exhibited exclusively the Z configuration. The difference may not be in the pathway used, but in the conditions used in the Wittig reaction (VII to VIII or XI to XII). It has also been found that the use of an appropriate lithium halide, such as, for example, lithium chloride, lithium bromide or lithium iodide, in the Wittig reaction gives an improvement in yield and purity.

2583757

  the product of the Wittig VIII (or XII) reaction. The reaction is preferably carried out with from 5 to 15 equivalents of lithium halide. If desired, the Z isomer of compound XIII (XIII (Z) in Scheme 3) can be converted to the corresponding E-isomer by photochemical reaction in the presence of a sensitizer. The reaction is usually

  carried out in a solvent selected from methanol, ethanol, propanol, ben-

  zene, toluene, acetone, acetonitrile, dichloromethane, DMF, acetate acetate,

  thyl, THF, pyridine, etc., in the presence of 0.5 to 10 equivalent (s) of a sensitizing agent selected from acetophenone, benzophenone, benzil, naphthalene, ethyl pyruvate, etc. In Figure 3, R4a represents a

  hydrogen atom or a benzhydryl radical.

  The deblocking of VIII (or XIV) to Ia is usually carried out using trifluoroacetic acid (TFA) in a suitable solvent in the presence of anisole. The resulting acid Ia was purified by reverse phase column chromatography using a glass column which contained the liner removed from a Waters' Associates PrepPAK-500 / C18 cartridge. The ester Ib can be prepared in a conventional manner, for example by reacting the acid Ia or a salt thereof (for example sodium, potassium, triethylammonium, etc.) with a halogenated compound of formula: R4-X wherein: X represents a chlorine, bromine or iodine atom; and R4 represents a group selected from

  -CH2OCOC (CH3) 3, -HOCOCH3, -CH2-C-CH3, -CH2COCO3

  CH3 0R 0 d 0 -CH HOC-OCH2CH3 or -CH. The reaction is carried out efficiently in an inert organic solvent, for example N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetone, acetonitrile, etc., at a temperature of between -10.degree. C. and + 50.degree. conveniently between 0 ° C. and 5 ° C. The ester Ib thus obtained is purified by conventional column chromatography using silica gel. Reaction Scheme 1 II! 2C1 COOCHPh2 TrNH-CCOOH TrNH-Ii IIa OR2a III IV TrNH-TrNH-s NaI or KI V PPh3 VI PPh3 N TrNH t 5 s I PPh3Y base N / N TrNH-I S VII COOCHPh2 t R3CH2CHo

N C -CONH

* N TrNHiN \ OR 2a CH-CHCH2R3 COOCHPh2 VIII

JTFA

% R: N t 7i CONH f

S \ OR2 H-CHCH2R3

  ## STR1 ## Reaction Scheme 2 SN * C 2 ci IZ PhCHO \ N1 /: H2Ci PPh3 X) 3c1 + COOCHPh2 base N / XI CH = PPh3 IX YM \ RrH 11.4 III X0

Oodo ---

IZiX T IX bZ O ir.DC) EI t7z

LSZú8SZ

Zoa. t ... 3 (a) h. '4, vzoS O XI

0 S] .NZ

  Z110I B ^ 000 HOOI (Z) iiDt- - 3.Zt: E UOIlDuei ap e-WaeS

> ZOO? ST

:, UOO RODN [H

  x-I WI S HOOD Iu RHDHDH NZ 'cuzzsH: = Res Y zen S S jazz ç JIHr'% .a toJN

1 Súú8 5

  ## STR5 ## C 'éE the' (E) 2 o 2co

OR2 00

EXAMPLE 1

  Diphenylmethyl-7-amino-3- (1-propenyl) -3-cephem-4-carboxylate (XIII, R3 = H)

  To a solution of diphenylmethyl-7-benzylideneamino-3-E (triphenyl-

  phosphoranylidene) methyl] -3-cephem-4-carboxylate (XI) (2.9 g, 4 mmol) in dichloromethane (16 ml), 90% acetaldehyde (10 ml,

  0.2 moles). The mixture is stirred at room temperature for 30 minutes.

  dried, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in ethyl acetate (80 ml). To this solution was added isopropyl ether (160 ml) and then silica gel (25 g). The mixture is gently shaken and filtered to remove the solid. The filtrate is evaporated to dryness in vacuo. To a solution of the residue in ethyl acetate (48 ml) is added a mixture of Girard reagent (1.34 g, 8 mmol), methanol (40 ml) and acetic acid (2 ml). The mixture is stirred

  the room temperature for 30 minutes and concentrated to about 10 ml.

  The residue is dissolved in ethyl acetate (100 ml). The solution is washed with aqueous sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column packed with silica gel (50 g) and eluted with 1% methanol in chloroform. The eluate is collected in 18 ml fractions. Fractions 22 to 40 are pooled and concentrated to give 718 mg of

  3-propenyl derivative XIII (R3 = H). (Yield 44%, E / Z = 1/3).

  TLC: Rf 0.56 (silica gel, ethyl acetate).

  HPLC: retention time (in min.) 13.2 and 15.6 (relative intensity 3/1)

IR: νmax (KBr) in cm-1 1770, 1720.

  UV: Xmax (C2H50H) in nm (c) 214 (20500), 222 (20800), 266 (4200),

273 (4200), 292 (3800).

27 2583757

  NMR (a 1/3 mixture of E and Z isomers): 6 (CDCl 3) in ppm: 1.42 and 1.72 (relative intensity = 3/1) (both are dd, I = 2 and 7 Hz, CH3); t 3.37 (ABq, I = 18 Hz, 2-H) and 3.52 (s, 2-H); 4.72 (d, II = 4.5 Hz, 6-H); 4.97 (d, I = 4.5 Hz, 7-H); 5.50 (dq, I = 7 and 11 Hz, = CH-); 6.06 (dd, I = 2 and 11 Hz, 3-CH =); 6.96 and 7.00 (3/1) (s, -OCHPh 2); 7.35 (s, phenyl-H). * packing: LIchrosorb RP-18 (4 x 300 mm). Nobile phase:

  CH3CN-H20 (1/1). flow rate: 2.5 ml / min.

EXAMPLE 2

  Diphenylmethyl-7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-

  (1-propenyl) -3-cephem-4-carboxylate (XIV, R = CH3, R3 = H)

  A mixture of diphenylmethyl-7-amino-3- (1-propenyl) -3-cephem-4-

  carboxylate (XIII, R3 = H) (3.37 g, 8.3 mmol) and del 1 - [(Z) -2- (2-amino)

  Thiazol-4-yl) -2-methoxyiminoacetoxy] benzotrial (2.64 g, 8.3 mmol) in THF (70 ml) is stirred at room temperature for 30 minutes and then evaporated in vacuo. A solution of the residue in ethyl acetate is washed successively with aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the crude product which is dissolved in the reaction mixture. chloroform and passed through column chromatography packed with silica gel (150 g) eluting with 2% methanol in CHCl 3. The desired fractions (TLC / silica gel, Rf 0.49, toluene / ethyl acetate 1/2) are combined and concentrated, giving 1.95 g (40%) of XIV (R 2 = CH 3, R 3 = H) [a

  1/2 mixture of isomers E and Z with respect to the configuration 3- (1propenyl)].

  NMR (a 1/3 mixture of E and Z isomers): 6 (CDCl 3) in ppm: 1.45 and 1.75 (relative intensity = 2/1) (both are d, I = 7 Hz, C-CH 3 ); 3.42 and 3.53 (2/1) (s, 2-H); 4.02 (s, OCH3); 5.13 (d, I = 4.5 Hz); 5.2-6.3 (m, 7-H)

  and vinyl-H); 6.73 (s, thiazole-H); 6.93 (s, OCHPhj); 7.30 (s, phenyl-H).

  * Hoechst, Japan Kokai 54-95593 (7/28/79) and German application 2,758,000

  (5/7/79) (German application P2758000.3 of December 24, 1977).

EXAMPLE 3

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyimfnoacetamido] -3- (1-

  propenyl) -3-cephem-4-carboxylic acid (Ia, R = CH3, R3 = H) The compound XIV (R2 = CH3, R3 = H) (1.9 g, 3.2 mmol) is treated with trifluoroacetic acid (TFA) (5 ml) at room temperature for 40 minutes. The mixture is diluted with isopropyl ether (IPE). The resulting precipitate is collected by filtration, dissolved in formic acid and passed through a packed column of 50 ml from a PrepPAK cartridge (Waters), washed with water and eluted with water. methanol to

  % and 20% methanol successively. Evaporation and freeze-drying

  The eluent with 15% methanol gives 206 mg (15%) of the title compound (E / Z = 1/17). Purity estimated at 90% (by HPLC). Melting point:> 180 C (slow dec).

  IR: V max (KBr) cm -1: 1770, 1660, 1630, 1530.

  UV: x max (pH 7 phosphate buffer) in nm (c) 228 (17400), 283 (16200).

  NMR: a (D 2 O + K 2 CO 3) in ppm: 1.70 (3H, d, I = 6 Hz, C-CH 3); 3.52 (2H, ABq, I = 18 Hz, 2-H); 4.03 (3H, s, OCH3); 5.28 (1H, d, I = 4.5 Hz, 6-H); 5,66,2

  (3H, m, 7-H and vinyl-H); 7.30 (1H, thiazole-H).

  HPLC: retention time 6.8 minutes (methanol-phosphate buffer pH 7,

1/3, 1.5 ml / min.).

  On analysis, we see that the product obtained has the formula:

C16H17N505S2-1 / 2H20

  b15 and the following values are obtained:

C H N S

  - calculated .......... 44.44 4.20 16.19 14.83 - found ............... 44.37 3.94 16.18 14.53

EXAMPLE 4

  Pivaloyloxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimilnoacetamido]

  3-E (Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 '= CH3, R3 = H, R4 = PV *)

  To a mixture of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino

  acetamido] -3- (1-propenyl) -3-cephem-4-carboxylic acid (Ia, R2 = CH3, R3 = H) (E / Z = 1/17, 90 mg, 0.21 mmol) and potassium (44mg,

  0.32 mol) in DMF (3 ml), pivaloyloxy iodide is added at 0 ° C.

  methyl (77 mg, 0.32 mmol). The mixture is stirred at 0 ° C. for 40 minutes, diluted with ethyl acetate (20 ml), washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue is dissolved in CHCl 3 and chromatographed on a column containing silica gel (silica gel: 3 g) and treated with 1% methanol in CHCl 3,

  which gives 85 mg (75%) of the title compound. Melting point: 100 ° C.

Estimated purity: 90% (by HPLC).

  IR: ν max (KBr) in cm 1: 1780, 1760, 1680, 1620.

  UV: Amax (methanol) in nm (ν) 232 (17800), 287 (13500).

  NMR: a (CDCl 3) in ppm: 1.23 (9H, s, C (CH 3) 3); 2.15 (3H, d, I = 7 Hz, CCH 3); 3.45 (2H, s, 2-H); 4.05 (3H, s, OCH3); 5.12 (1H, d, I = 4.5 Hz, 6-H); , 6-6.2 (5H, m, 7-H, vinyl-H and -OCH 2 O-); 6.85 (1H, s, thiazole-H).

  HPLC: retention time 8.1 minutes (CH3CN-H20 1/1, 2 ml / min.).

I

* PV: -CH20CC (CH3) 3

EXAMPLE 5

  1-acetoxyethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3E (Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = H, R4 = AX *)

  A mixture of 7-E [(Z) -2- (2-aminothiazol-4-yl) -2-methoxylmino

  acetamido] -3- (1-propenyl) -3-cephem-4-carboxylic acid (190 mg, 0.45 mmol) and potassium carbonate (75 mg, 0.54 mmol) in DMF (5 mL), 1-Bromoethyl acetate (90 mg, 0.54 mmol) is added at 5 ° C. The mixture is stirred at 5 ° C. for 1.5 hours and diluted with ethyl acetate (20 ml). The diluted product is washed successively with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is dissolved in chloroform and chromatographed on a column containing silica gel (5 g) eluting with 1% methanol in chloroform. The desired fractions are pooled and concentrated. The residue was dissolved in dioxane and lyophilized to give 103 mg (45%) of the title compound as its solvate in dioxane. Melting point: 105-110 C. Purity

estimated: 85% (by HPLC).

  IR: ν max (KBr) in cm 1: 1760 (br.), 1670, 1610.

  UV: Xmax (ethanol) in nm (υ) 233 (15700), 292 (12800).

  NMR: δ (CDCl 3) in ppm: 1.50 (3H, d, I = 6 Hz, OCHCH 3); 1.65 (3H, d, I = 7Hz, = CH-CH3); 2.07 (3H, s, COCH3); 3.43 (2H, s, 2-H); 3.68 (4H, s, 1/2 dioxane); 4.05 (3H, s, OCH3); 5.10 (1H, d, I = 4.5 Hz, 6-H); 5.5-6.0 (2H, m, 7-H and = CH-CH3); 6.12 (1H, d, I = 12 Hz, 3-CH =); 6.83 (1H, s, thiazole-H); 6.98

(1H, q, I = 6 Hz, OCHO).

  HPLC: retention time 7.5 minutes (CH3CN-H20 1/1, 1 ml / min.).

* AX = -CH (CH3) OCOCH3

  ** E. Buckley and E. Whittle, Can. J. Chem., 40, 1611 (1962).

EXAMPLE 6

  Diphenylmethyl-7-amino-3 - [(Z) -1-butenyl] -3-cephem-4- hydrochloride

  carboxylate (XIII, R3 = CH3, hydrochloride) To a solution of propionaldehyde (10.7 g, 18 mmol) and lithium iodide (13.4 g, 10 mmol) in a DMF / CH2Cl2 mixture (50 ml / 150 ml), XI (7.3 g, 10 mmol) is added at 0 ° C. The mixture is left standing at 5 ° C. for 2 days and concentrated in vacuo. A solution of the residue in ethyl acetate (200 ml) is washed with water, dried over MgSO4 and evaporated in vacuo to a syrup which is treated with CCl4 (200 ml) and filtered. The filtrate is concentrated to about 50 ml and the concentrate is stirred in the presence of 6N HCl (4 ml) at room temperature for 30 minutes. The resulting precipitate is collected by filtration and recrystallized from CHCl 3 -ethyl acetate to give 1.49 g (33%) of the mixture.

  composed in section. Melting point: 120-127 C.

IR: νmax (KBr) in cm 1: 1780, 1710.

  UV: λmax (methanol) in nm (e) 217 (13900), 286 (7400).

  NMR: δ (DMSO-d6) in ppm: 0.93 (3H, t, I = 7 Hz, CH3); 2.00 (2H, m, C 2 CH 3); 3.75 (2H, ABq, I = 16 Hz, 2-H); 5.1-5.9 (3H, m, 6-H and 7-H, = CH-CH 2 -); 6.33

  (1H, d, I = 12 Hz, 3-CH =); 6.97 (1H, s, -CHPh 2); 7.40 (10H, s, phenyl-H).

  HPLC: retention time (minutes) 10.4 and 12.0 (relative intensity = 8/1)

  (methanol / phosphate buffer pH 7.4 / 1, 1 ml / min.).

EXAMPLE 7

  Diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-méthoxyiminoacétamidoJ-

  3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate (XIV, R 2 = CH 3, R = CH 3)

  A suspension of diphenylmethyl-7-amino-3-E (Z) -1-chlorohydrate

  Butenyl] -3-cephem-4-carboxylate (1.41 g, 3.1 mmol) in ethyl acetate (20 ml) is shaken in the presence of NaHCO3 to give a clear two-layer solution. Separate the organic layer, wash with

  water and then with saturated NaCl solution and dried over MgSO4.

  To the dried filtrate, 1 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy) is added.

  iminoacetoxy] benzotriazole (1.27 g, 4.0 mmol) and the mixture is stirred at room temperature for 20 hours. The reaction mixture is filtered and the filtrate is washed with aqueous NaHCO3, water and saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The residue is chromatographed on a column of silica gel (40 g), eluting with a 3: 1 CHCl 3 / ethyl acetate mixture to give 1.7 g (91%) of the title compound.

  heading. TLC (silica gel): Rf 0.25 (1: 1 CHCl3 / ethyl acetate).

  IR: ν max (KBr) in cm 1: 1780, 1720, 1680, 1620.

  UV: Xmax (ethanol) in nm ({) 288 (12400).

  NMR: δ (CDCl 3) δ ppm: 0.86 (3H, t, I = 7 Hz, -CH 3); 1.90 (2H, m, C.2CH3); 3.45 (2H, s, 2-H); 4.06 (3H, s, OCH3); 5.15 (1H, d, I = 4.5 Hz, 6-H); 5.45 (1H, dt, I = 7 and 11 Hz, = CH-CH 2 -); 6.05 (1H, dd, I = 4.5 and 9 Hz, 7-H); 6.17 (1H, d, I = 11 Hz, 3-CH =); 6.75 (1H, s, thiazole-H); 6.97 (1H, s,

  CHPh 2); 7.35 (10H, s, phenyl-H); 8.08 (1H, d, I = 9 Hz, CONH).

31 2583757

EXAMPLE 8

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z)] acid

  1-butenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH3, R3 = CH3)

  A mixture of diphenylmethyl-7-r (Z) -2- (2-aminothiazol-4-yl) -2-methoxy-

  iminoacetamidol-3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate (1.65 g, 2.65 mmol) and anisole (0.5 ml) is treated with TFA ( 5 ml) at room temperature for 1 hour. The mixture is diluted with IPE. We collect

  precipitate1 which results from filtration and is chromatographically

  on a packed column (50 ml) of a PrepPAK cartridge (Waters) eluting with 20-30% methanol to give 605 mg (52%) of the compound

  heading. Estimated purity: 90% (by HPLC). Melting point:> 160 ° C (dec.

prog.).

  IR: V max (KBr) in cm -1: 1760, 1670, 1650, 1620.

  UV: Xmax (pH 7 phosphate buffer) in nm (c) 232 (16200), 283 (15500).

  NMR: 6 (D20 + NaHCO3) in ppm: 1.00 (3H, t, I = 7 Hz, CH3); 2.00 (2H, dq, I = 7 and 7 Hz, -CH 2 CH 3); 3.52 (2H, Abq, I = 17Hz, 2-H); 4.02 (3H, s, OCH3); 5.27 (2H, d, I = 4.5 Hz, 6-H); 5.4-6.1 (3H, m, 7-H and -CH = CH-); 7, 00

(1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C17H19N505S2. 1 / 2:20

  and the following values are obtained:

C H N S

  - calculated .......... 45.73 4.51 15.69 14.36 - found ........... 45.41 4.23 15.35 14.21 1HPLC : retention time (minutes) 5.0 and 6.4 (relative intensity =

  8/1) (methanol / phosphate buffer pH 7 3/7, 2 ml / min.).

EXAMPLE 9

  Pivaloyloxymethyl-7-r (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 = PV *) Pivaloyloxymethyl iodide (162 mg, 0.67) is added mmol) 0O C

  to a mixture of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamidol-3 - [(Z) -1-butenyl] -3-cephem-4-carboxylic acid ( 197 mg, 0.45 mmol)

  and K2CO3 (93 mg, 0.67 mmol) in DMF (4 mL). The mixture is stirred at 0.degree. C. for 1 hour and diluted with ethyl acetate (30 ml). The diluted product is washed with water and saturated NaCl solution, dried over anhydrous MgSO4 and evaporated in vacuo. The residue is chromatographed on a column packed with silica gel (5 g), eluting with

32 2583757

  with 1% methanol in CHCl3. The desired fractions are collected

  concentrated and concentrated under vacuum. The residue is dissolved in dioxane and lyophilized to give 242 mg (97%) of the solvated title compound in the

  dioxane. TLC suo: silica gel Rf 0.25 (CHCl3 / ethyl acetate 1/1).

  Estimated purity: 85% (by HPLC). Melting point: 90-95C.

  IR: ν max (KBr) in cm -1: 1780, 1750, 1670.

  UV: xmax (ethanol) in nm (C) 233 (15300), 285 (11300).

  NMR: δ (CDCl 3) in ppm: 0.97 (3H, t, I = 7 Hz, CH 2 CH 3); 1.23 (9H, s, C (CH3) 3); 2.03 (2H, dq, I = 7 and 7 Hz, -CH 2 CH 3); 3.43 (2H, s, 2-H); 3.67 <4H, s, 1/2 dioxane); 4.02 (3H, s, OCH3); 5.10 (1H, d, I = 4.5 Hz, 6-H); 3-6.3 (5H, m, 7-H, -CH = CH- and -OCH 2 O-); 6.82 (1H, s, thiazole-H); 7.97

(1H, d, I = 8 Hz, CONH).

  HPLC: retention time, 10.0 minutes (CH3CN / H2O 1/1, 2 ml / min.) On analysis, it is found that the product obtained has the formula:

C23H29N507S2. 1 / 2C4H802

  and the following values are obtained:

C H N S

  - calculated .......... 50.41 5.58 11.76 10.76 - found ............... 49.94 5.57 11.56 10.76

* PV = -CH20COC (CH3) 3

EXAMPLE 10

  1-acetoxyethyl-7- [E (Z) -2- (2-aminothiazol-4-yl) -2-methoxylminoacetamido]

  3-r (Z) -1-butenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 = AX *)

  To a mixture of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino

  3-acetamido-3 - [(Z) -1-butenyl-3-cephem-4-carboxylic acid (1.55 g, 3.54 mol) and K 2 CO 3 (636 mg, 4.6 mmol) in DMF (4 ml) 35 C of 1-bromoethyl acetate (769 mg, 4.6 mmol) is added. The mixture is stirred at 5 ° C. for 1 hour, diluted with ethyl acetate (300 l), washed with water, dried over anhydrous MgSO 4 and concentrated in vacuo. The residue is dissolved in chloroform and chromatography is carried out on a column

  packed with silica gel (50 g) eluting with 1% methanol in CHCl 3.

  The desired fractions are pooled and concentrated to a small volume.

  Triturate the residue in the presence of isopropyl ether to give 1.9 g (70%)

  of the title compound as a solvent in isopropyl ether.

  Estimated purity: 90% (by HPLC). Melting point: 103-110 ° C (dec.).

  IR: ν max (KBr) cm -1: 1770 (br.), 1670, 1620.

  UV: X max (ethanol) in nm (e) 233 (14300), 288 (11000).

  NMR: δ (CDCl 3) in ppm: 1.00 (3H, t, I = 7 Hz, -CH 2 CH 3); 1.12 (12H, d, I = 6 Hz, isopropyl ether CH 3); 1.53 (3H, d, I = 5 Hz, OCHCH3); 1.95 (2H, m,

  CCH2CH3); 2.08 (3H, s, COCH3); 3.43 (2H, s, 2-H); 3.62 (2H, m, isopropyl-

  ether CH); 4.08 (3H, s, OCH3); 5.13 (1H, d, I = 4.5 Hz, 6-H); 5.2-6.2 (3H, m, 7-H and -CH = CH-); 6.87 (1H, s, thiazole-H); 7.00 (1H, q, I = 5 Hz,

-CHCH3).

  HPLC: retention time, 10.8 minutes (CH3CN / H2O 1/1, 1 ml / min.) On analysis, it is found that the product obtained has the formula:

C21H25N507S2.C6H140

  and the following values are obtained:

C H N S

  - calculated .......... 51,83 6,28 11,19 10,25 - found ........... 51,62 6,07 11,16 10,05

* AX = -CH (CH3) OCOCH3

EXAMPLE 11

  Diphenylmethyl-7-E (Z) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) -

  acetamido] - 3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylate (XIII, R2a = CH R3 Ra = CH3, R3 = OCH3)

  A solution of diphenylmethyl-7-E (Z) -2-methoxyimino-2 iodide

  (2-tritylaminothiazol-4-yl) acetamido] -3-triphénylphosphoniométhyl-3-

  cephem-4-carboxylate (1.19 g, 1 mmol) in CH2Cl2 (30 mL) is shaken into

  presence of 1N NaOH (5 ml) for 2 minutes. Separate the organic layer

  The mixture is washed with water and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and filtered. To the filtrate, add

  isopropyl alcohol (15 ml) and methoxyacetaldehyde (7.41 mg, 10 mmol

  the). The mixture is stirred at room temperature overnight and evaporated to dryness in vacuo. The residue is dissolved in CHCl 3 and chromatographed on a column packed with silica gel (20 g) eluting with 1/20 ethyl acetate / toluene, which gives

  570 mg (66%) of the title compound.

  IR: V max (KBr) in cm: 1775, 1720, 1670, 1525, 1175.

  NMR: δ (CDCl 3 + D 2 O) in ppm: 3.24 (3H, s, OCH 3); 3,3-3,8 (4H, m, S-CH 2 and OCH 2); 4.13 (3H, s, NOCH3); 5.15 (1H, d, I = 4.5 Hz, 6-H); 5.98 (1H, d, I = 4.5 Hz, 7-H); 6.3 (1H, d, I = 11 Hz, vinyl-H); 6.8 (1H, s, thiazole-H);

  6.98 (1H, s, CHPh 2); 7.1-7.5 (25H, phenyl-H).

  HPLC: retention time 13.6 minutes (CH3CN / H20 3/1, 1 ml / min.)

EXAMPLE 12

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -3-) acid

  methoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH3, R3 = OCH3). The mixture is left at room temperature for 50 minutes.

  solution of diphenylmethyl-7 - [(Z) -2-methoxyimino-2- (2-tritylaminothiazol)

  4-yl) acetamido] -3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylate (550 mg, 0.64 mmol) in anisole / TFA (0.5 ml) / 5 ml) and diluted with

  isopropyl ether to obtain a precipitate which is collected by filtration.

  and washed with IPE. The solid is dissolved in methanol and chromatographed on a column packed (40 ml) from a PrepPAK cartridge (Waters) eluting with 30% methanol to give 104 mg (36%). of the title compound. Melting point: 155-159 ° C

  (Dec.). Estimated purity: 90% (by HPLC).

  IR: V max (KBr) in cm ': 1765, 1660, 1630, 1530, 1040.

  UV: X max (methanol) in nm (e) 234 (16600), 287 (14500).

  NMR: δ (DMSO-d6 + D20) δ ppm: 3.19 (3H, s, OCH3); 3.83 (3H, s, OCH3); 5, 17 (1H, d, I = 5 Hz, 6-H); 5.4-5.8 (1H, m, vinyl-H); 5.72 (1H, d, I = 5 Hz,

  7-H); 6.27 (1H, d, I = 12 Hz, vinyl-H); 6.72 (1H, s, thiazole-H).

  HPLC: retention time 9.6 minutes (methanol / phosphate buffer pH 7, 1/3, 1 ml / min.) On analysis, it is found that the product obtained has the formula:

C17H19N506-H20

  and the following values are obtained:

C H N S

  - calculated .......... 43.30 4.49 14.85 13.60 - found ........... 43.04 4.09 14.59 13.89

EXAMPLE 13

  Pivaloyloxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R = CH 3,

R3 = OCH3, R4 = PV)

  Esterification of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy)

  iminoacetamido] -3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylic acid (226 mg, 0.5 mmol) similarly to that described in Example 9

  gives the title compound (87 mg, 34%). Melting point: 100-102 C.

  Estimated purity: 90% (by HPLC, methanol / phosphate buffer pH 7, 1/1).

  IR: V max (KBr) in cm -1: 1775, 1750, 1670, 1530, 1370, 1120.

  UV: λmax (methanol) in nm (Ec) 232 (16600), 289 (13500).

  NMR: 6 (DMSO-d 6 + D 2 O) in ppm: 1.18 (9H, s, 3 x CH 3); 3.19 (3H, s, OCH3); 3.57 (2H, br., SCH2); 3.85 (3H, s, OCH3); 5.23 (1H, d, I = 5 Hz, 6-H); 5, 4-5.9 (4H, m, 7-H, OCH 2 O and vinyl-H); 6.24 (1H, d, I = 12 Hz, vinyl-H);

6.74 (1H, s, thiazole-H).

EXAMPLE 14

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R = CH 3,

R = OCH3, R = AX)

  Esterification of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy)

  iminoacetamido] -3 - [(Z) -3-methoxy-1-propenyl] -3-cephem-4-carboxylic acid (300 mg, 0.66 mmol) with 1-bromoethyl acetate, in the same manner as that described in Example 10 gives the title compound (154 mg, 43%). Melting point: 102-105 ° C (dec). Estimated purity: 95% (by HPLC,

  CH3CN / phosphate buffer pH 7, 1/1).

  IR: V max (KBr) in cm -1: 1775-1760, 1670, 1530, 1375.

  UV: X max (methanol) in nm (c) 232 (15900), 288 (13000).

  NMR: a (CDCl3 + D20) in ppm: 1.51 (3H, d, I = 5 Hz, CHCH3); 2.07 (3H, s, COCH3); 3.29 (3H, s, CH 2 OCH 3); 3.45 (2H, br, S-CH 2); 3.87 (2H, d, I = 7 Hz, = CHCH 2 O); 4.04 (3H, s, NOCH3); 5.09 (1H, d, I = 5 Hz, 6-H); 55-5.9 (1H, m, vinyl-H); 5.97 (1H, d, I = 5 Hz, 7-H); 6.8 (1H, d, I = 12 Hz, vinyl-H); 6.83 (1H, s, thiazole-H); 6.97 (1H, q, I = 5 Hz,

OCHCH3).

EXAMPLE 15

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(E) -1-) acid

  butenyl] -3-cephem-4-carboxylic acid (la, R = CH3, R = CH3, isomer E)

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy)

  iminoacetamido] -3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate which was obtained in Example 7 (7.6 g, 1.3 mmol), TFA (25 ml). ) and anisole (5 ml) is stirred at 5 ° C for 1 hour and diluted with isopropyl ether. The resulting precipitate is collected by filtration, dissolved in formic acid and purified by preparative HPLC (Waters, System 500, PrepPAK-500 / C18) eluting with 40% methanol. The eluate was monitored by analytical HPLC and split into two fractions, which were evaporated in vacuo to give 0.94 g of the Z isomer of Ia (R2 = CH3, R3 = CH3) and 1.65. g of a mixture of the Z isomer and the corresponding E isomer. The mixture is dissolved in formic acid and chromatographed on a column packed (50 ml) from a PrepPAK (Waters) cartridge.

  eluting with 20 to 30% methanol to give 0.22 g (4%) of

  mother E at the same time as 0.90 g of the Z isomer. Estimated purity: 90% (by HPLC). Melting point:> 170 C (Dec. prog.).

IR: ν max (KBr) in cm 1: 1760, 1660.

  UV: kmax (pH 7 phosphate buffer) in nm (c) 232 (15400), 292 (19400).

  NMR: 6 (D20 + NaHCO3) in ppm: 1.18 (3H, t, I = 7Hz, CH2CH3); 2.30 (2H, m, CHCH3); 3.83 (2H, s, 2-H); 4.15 (3H, s, OCH3); 5.37 (1H, d, I = 5 Hz, 6H); 5.93 (1H, d, I = 5 Hz, 7-H); 5.9-6.4 (1H, m, = CHCH2); 5.66 (1H, d,

  I = 16 Hz, 3-CH =); 7.18 (1H, s, thiazole-H).

  HPLC: retention time 6.4 minutes (methanol / phosphate buffer pH 7, 3/7, 2.0 ml / min.)

EXAMPLE 16

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(E) -1-butenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 = AX, E isomer)

  To a mixture of 7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino

  acetamido] -3-E (E) -1-butenyl] -3-cephem-4-carboxylic acid (130 mg, 0.3 mmol) and K 2 CO 3 (55 mg, 0.4 mmol) in DMF (2.5 ml) is added at 5 ° C 1-bromoethyl acetate (67 mg, 0.4 mmol). The mixture is stirred at 5 ° C. for 1 hour. It is diluted with ethyl acetate (25 ml), washed successively with water and with aqueous NaCl solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue is dissolved in chloroform and chromatographed on a column filled with gel.

of silica eluting with 1% methanol in CHCl 3. The fractions sought

  The samples are pooled and concentrated in vacuo to give 77 mg (49%) of the title compound. Estimated purity: 90% (by HPLC). Fusion point:

-115 C.

  IR: ν max (KBr) in cm -1: 1760 (br.), 1670, 1510.

  UV: X max (methanol) in nm (c) 232 (15100), 298 (17000).

  NMR: δ (CDCl 3) in ppm: 1.05 (3H, t, 1 = 7Hz, CH 2 CH 3); 1.54 (3H, d, I = 6Hz, CHCH3); 3.08 (3H, s, COCH3); 2.0-2.4 (2H, m, -CH 2 CH 3); 3.57 (2H, s, 2H); 4.05 (3H, s, OCH3); 5.07 (1H, d, I = 5 Hz, 6-H); 5.8-6.3 (2H, m,

  7-H and = CH-CH 2 -); 6.86 (1H, s, thiazole-H); 6.8-7.1 (2H, m, OCH and 3-CH =).

  HPLC: retention time 7.7 minutes (CH3CN / H20 1/1, 1.5 ml / min.)

EXAMPLE 17

  Acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3-E (Z) -1-butenyl] -3-cephem-4-carboxylate (Ib, R 2 = CH 3, R 3 = CH 3, R = CHOCOCH 3, Z-isomer)

  To a mixture of 7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyimino acid

  acetamido] -3-E (Z) -1-butenyl] -3-cephem-4-carboxylic acid (300 mg, 0.69 mmol) and K2CO3 (95 mg, 0.69 mmol) in dry DMF (3 mL ), a solution of bromomethyl acetate (105 mg, 0.69 mmol) in dry DMF (0.25 ml) is added dropwise at 0 ° C. The reaction mixture is stirred for a further minute and diluted with ethyl acetate (20 ml). The diluted product is washed with water and saturated NaCl solution, dried over anhydrous Na 2 SO 4 and evaporated to dryness. The residue is dissolved in methanol and passed over a column packed (40 ml) from a PrepPAK cartridge (Waters), washed with water and then eluted with 50% methanol. The eluate is monitored by HPLC, the fractions are collected

  and evaporated to give 96 mg (27%) of the title compound.

  Estimated purity: 90% (by HPLC). Melting point: 149-152 C.

  IR: ν max (KBr) in cm -1: 1780, 1660, 1535, 1375, 1170, 1045.

  UV: X max (methanol) in nm (e) 231 (17000), 289 (13100).

  NMR: δ (CDCl 3 + D 2 O) in ppm: 0.99 (3H, t, I = 7.2 Hz, CH 3); 2.11 (3H, s, COCH3); 1.75-2.5 (2H, m, CH 2 CH 3); 3.45 (2H, s, S-CH 2); 4.05 (3H, s, OCH3); 11 (1H, d, I = 4.5 Hz, 6-H); 5.81 (2H, s, OCH 2 O); 5.99 (1H, d, I = 4.5 Hz,

  7-H); 6.18 (1H, d, I = 12 Hz, 3-CH); 6.76 (1H, s, thiazole-H).

  HPLC: retention time 6.3 minutes (CH3CN / phosphate buffer pH 7, 3/2) On analysis, it is found that the product obtained has the formula:

C20H23N507S2. 1 / 2:20

  and the following values are obtained:

C H N S

  - calculated .......... 46.32 4.66 13.50 12.37 - found ........... 46.51 4.44 13.34 12.25

EXAMPLE 18

  4- [N- (t-butoxycarbonyl) glycyloxy] benzoyloxymethyl-7 - [(Zl-2- (2 aminothiazol

  4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 = BOC-GBM *)

  A solution of chloromethyl-4- [N- (t-butoxycarbonyl) glycyloxy] -

  benzoate (584 mg, 1.7 mmol) in acetone (10 ml) is stirred in the presence of sodium iodide (1.28 g, 8.5 mmol) at room temperature

38 2583757

  for 6 hours. The sodium chloride that separates is removed by filtration. The filtrate is concentrated under vacuum. The residue is dissolved in dimethylformamide (10 ml) and added at -20 ° C. to an acidic mixture.

  7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -1-butenyl] -

  3-Cephem-4-carboxylic acid (437 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol) in dimethylformamide (5 ml). The mixture is stirred at 0 ° C. for 1 hour, dissolved with ethyl acetate (50 ml), washed successively with water and with an aqueous solution of sodium chloride, dried over sulfate. of anhydrous magnesium and concentrated in vacuo. The residue is chromatographed on a column packed with silica gel (20 g) eluting with 1/1 toluene / ethyl acetate to give 533 mg (76%) of the title compound. TLC (silica gel): Rf 0.16

  (toluene / ethyl acetate 1/1). Melting point: 110-117 C.

  IR: V max (KBr) cm -1: 1770, 1740, 1670.

  UV: kmax (methanol) in nm (c) 237 (26700), 287 (11800).

  NMR: δ (CDCl3 + O20) in ppm: 0.90 (3H, t, I = 7Hz, CH2CH3); 1.48 (9H, s, C (CH3) 3); 2.00 (2H, dq, I = 7 and 7 Hz, CH 2 CH 3); 3.43 (2H, s, 2-H); 3.98 (3H, s, OCH3); 4.13 (2H, s, CH 2 NH); 5.10 (1H, d, I = 4.5 Hz, 6-H); 5.50 (1H, dt, I = 11 and 7 Hz); 5.9-6.3 (4H, m, 7-H, vinyl-H and OCH 2 O); 6.52 (1H,

  s, thiazole-H); 7.17 and 8.06 (each 2H, d, I = 8 Hz, benzene-H).

  * BOC-GBM = -CH20CO- O COCH2NHCOOC (CH3) 3

EXAMPLE 19

  4-glycyloxybenzoyloxymethyl-7 - [(Z) -2- (2-aminothiazol) dihydrochloride

  4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -1-butenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH3, R4 = GBM *, hydrochloride) A mixture of N (t-butoxycarbonyl) derivative (349 mg, 0.5 mmol) obtained in Example 18, anisql (3 drops) and 2N hydrochloric acid in ethyl acetate (2.5 ml) is stirred at 5 ° C. for 15 minutes. The resulting precipitate is collected by filtration and dissolved in methanol (3 ml). After filtration, ethyl acetate (39 ml) was added to the filtrate. The resulting precipitate is collected by filtration, which

  gives 166 mg (46%) of the title compound. Melting point:> 160 ° C (dec).

Estimated purity: 90% (by HPLC).

  IR: ν max (KBr) cm -1: 1780, 1745, 1670, 1630.

  UV: -max (methanol) in nm (c) 235 (27200), 287 (12900).

  NMR: δ (DMSO-d6) in ppm: 0.78 (3H, t, I = 7 Hz, CH 2 CH 3); 2.00 (2H, m, CH 2 CH 3); 3.52 (2H, s, 2-H); 3.90 (3H, s, OCH3); 4.05 (2H, s, CH 2 NH); 5.22

39 2583757

  (1H, d, I = 5 Hz, 6-H); 5.5-6.2 (5H, m, 7-H, vinyl-H x 2 and OCH 2 O); 6.88

  (1H, s, thiazole-H); 7.35 and 8.00 (each 2H, d, I = 8 Hz, benzene-H).

  On analysis, we see that the product obtained has the formula:

C27H28N609S2. 1 / 2:20

  and the following values are obtained: CHNS Cl - calculated .......... 44, 63 4.30 11.57 8.82 9.76 - found ........... 44 , 69 4.34 11.13, 8.46, 9.18 HPLC: retention time 5.2 minutes (CH3CN / H2O 3/2, 1 ml / min.) = -C 2Oco o ODCO32

EXAMPLE 20

  Diphenylmethyl-7-amino-3- (1-pentenyl) -3-cephem-4-carboxylate (XIII,

R3 = CH2CH3)

  To a cooled, stirred solution of 8.7 g (0.1 mole) of anhydrous lithium bromide in 50 ml of DMF, a solution of 7.3 g (0.01 mole) of the solution is added in one portion. ylide (XI) in 250 ml of methylene chloride. To the solution was added 30 ml of n-butyraldehyde and the mixture was stirred at room temperature for 24 hours. After concentration to ml, the residue is extracted with 300 ml of ethyl acetate. The extract is washed with water and saturated NaCl solution and dried over anhydrous MgSO4. Wako-gel (C-100, 10 g) and activated charcoal (1 g) were added. The mixture is filtered and the filtrate is concentrated to 100 ml. To the filtrate, 5 g (0.03 mol) of Girard T in 100 ml of methanol containing 1 ml of acetic acid are added and the mixture is stirred at room temperature for 30 minutes. After evaporation to dryness, the mixture is extracted with 300 ml of ethyl acetate. The extract is washed successively with water, aqueous sodium bicarbonate solution, water and saturated NaCl solution and dried over anhydrous MgSO4. After evaporation to dryness, the residue is chromatographed on a column of silica gel (Merck Kieselgel 60, 120 g) eluting with toluene / ethyl acetate (5/1). The desired fractions collected by TLC monitoring are evaporated to dryness, yielding 1.78 g (41%) of the compound.

  heading in the form of expanded solid.

  NMR: 6 (CDCl 3) in ppm: 0.7-2.0 (7H, m, CH 2 x 2 and C-CH 3); 3.28 (1H, d, I = 18 Hz, 2-H); 3.53 (1H, d, I = 18 Hz, 2-H); 4.75 (1H, d, I = 4.5 Hz, 6-H); 5.01 (1H, d, I = 4.5 Hz, 7-H); 5.2-5.7 (1H, m, CH = C); 6.12 (1H, d,

  I = 11 Hz, 3-OH = C); 7.00 (1H, s, CHPh 2); 7.2-7.6 (1OH, m, phenyl-H).

2583757

EXAMPLE 21

  Diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido]

  3- (1-Pentenyl) -3-cephem-4-carboxylate (XIV, R2 = CH3, R3 = CH2CH3) A mixture of 1.7 g (3.9 mmol) of XIII (R3 = CH2CH3) and 1.24 g (3.9 mmol) of 1- (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] benzotriazole in 150 ml of ethyl acetate is stirred at room temperature for 20 minutes. hours and the mixture is evaporated to dryness. The residue is chromatographed on a column packed with silica gel (Merck Kieselgel 70, 60 g) eluting successively with chloroform and 1% methanol in chloroform. The desired fractions eluted in the chloroform / methanol mixture and monitored by TLC gel

  silica (MeOH / CHCl3 1/15, Rf 0.50) are collected and evaporated to dryness.

  Triturate the residue in the presence of ether-isopropyl ether to give 1.94 g (85%) of the title compound, mp 115-120 ° C.

(Dec.).

  IR: max (KBr) in cm -1: 1775, 1720, 1670, 1610, 1530, 1380, 1220, 1180, 1030.

  UV:) max (methanol) in nm (υ) 290 (14000).

  NMR: δ (CDCl 3) in ppm: 0.6-2.1 (2H, m, CH 2 and CH 3); 3.42 (2H, br-s, 2H); 4.04 (3H, s, OCH3); 5.15 (1H, d, I = 4.5 Hz, 6-H); 5.3-5.8 (3H, m, CH = O and NH 2); 6.02 (1H, d-d, I = 4.5 and 8 Hz, 7-H); 6.15 (1H, d, I = 11 Hz, 3-CH = 0); 6.80 (1H, s, thiazole, H); 6.98 (1H, s, CHPh 2); 7.2-7.5 (1OH, m,

  phenyl-H); 8.0 (1H, d, I = 8 Hz, NH).

EXAMPLE 22

  7- [E (Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -1-) acid

  pentenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH3, R3 = CH2CH3, Z-isomer) A mixture of 2.5 g (4.27 mmol) of XIV (R2 = CH3 'R3 = CH2CH3),

  2.5 ml of anisole and 7.5 ml of trifluoroactic acid are stirred at room temperature.

  room temperature for 10 minutes and concentrated to 3 ml. The residue is diluted with 100 ml of isopropyl ether to give 2 g of trifluoroacetate of the title compound (5/1 mixture of Z and E isomers). Dissolve

  crude product in aqueous methanol and the solution is

  column chromatography containing a lining from a PrepPAK C-18 cartridge (Waters, 300 ml) and eluted successively with water,

  10% methanol, 20% methanol, 30% methanol and 40% methanol.

  The eluate is monitored by HPLC. Fractions containing the Z isomer of the eluate in 40% methanol are collected and evaporated to dryness and the solid residue is dissolved in methanol and filtered. To the filtrate is added 200 ml of isopropyl ether and the resulting solid is collected by filtration, washed with isopropyl ether and dried under vacuum over P2O5.

  which gives 695 mg (39%) of product, which is 90% pure, this being

  by HPLC. Melting point: 150-155 ° C (dec).

  IR: ν max (KBr) cm -1: 1770, 1670, 1630, 1530, 1370, 1180, 1040.

  UV: kmax (pH 7 phosphate buffer) in nm (c) 228 (16000), 283 (15000).

  NMR: 6 (D20 + Na2CO3) in ppm: 1.01 (3H, t, I = 7Hz, CH2CH3); 1.3-1.7 (2H, m, CH 2 CH 2 CH 3); 2.0-2.3 (2H, m, = CH-CH2-CH2); 3.56 (1H, d, I = 18 Hz, 2-H); 3.76 (1H, d, I = 18 Hz, 2-H); 4.15 (3H, s, OCH3); 5.38 (1H, d, I = 4.5 Hz, 6-H); 5.5-5.9 (1H, m, CH = C); 5.92 (1H, d, I = 4.5 Hz, 7-H); 6.09 (1H, d,

  I = 11 Hz, 3-CH = 0); 7.16 (1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C18H21N505S2. 1 / 2:20

  and the following values are obtained:

C H N S

  - calculated ....... 46.94 4.82 15.21 13.92 - found ....... 46.93-47.04 4, 66-4.71 15.00-15, 00 13.34-13.36 HPLC: retention time 9.9 minutes (MeOH / phosphate buffer at pH 7, 2/3, 1 ml / min.)

EXAMPLE 23

  7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-E (E) -1-

  pentenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH3, R3 = CH2CH3, isomer E) The fractions containing the E-isomer of the eluate in 40% methanol (see Example 22) were collected and evaporated to dryness, giving 455 mg of a mixture of cis and trans isomers (1/1). The crude product was re-chromatographed on a packed column from a PrepPAK C-18 cartridge (Waters, 300 ml) eluting with 35% methanol and monitored by HPLC. The desired fractions containing the trans-isomer are collected and concentrated to 10 ml and lyophilized to give 89 mg (5%) of product which is 75% pure, this being found by

  HPLC. Melting point: 180 ° C. (Dec. prog.)

  IR: νmax (KBr) in cm 1: 1770, 1660, 1630, 1530, 1380, 1040.

max

  UV: X max (pH 7 phosphate buffer) in nm (c) 228 (17000), 292 (22000).

  NMR: δ (D 2 O + Na 2 CO 3) in ppm: 1.05 (3H, t, 1 = 7Hz, CH 2 CH 3); 1.2-1.8 (2H, m, CH 2 CH 2 CH 3); 2.1-2.5 (2H, m, = CH-CH2CH2); 3.81 (2H, s, 2-H); 4.16 (3H, s, OCH3); 5.37 (1H, d, I = 4.5 Hz, 6-H); 5.91 (1H, d, I = 4.5 Hz, 7-H); 9-6.3 (1H, m, CH = C); 6.67 (1H, d, I = 16 Hz, 3-CH = C); 7.17 (1H, s, thiazole-H). HPLC: retention time 12.3 minutes (MeOH / phosphate buffer at pH 7, 2/3, 1 ml / min.)

EXAMPLE 24

  1-acetyloxy-7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3-E (Z) -1-pentenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = CH2CH3, R4 = AX, Z isomer) To a stirred mixture of Ia (R2 = CH3, R3 = CH2CH3, isomer Z) (225 mg, 0.5 mmol) and 69 mg (0.5 mmol) of potassium carbonate in 5 ml of DMF,

  a solution of 84 mg (0.5 mmol) of acetoxy bromide is added at 0 ° C.

  ethyl in 1 ml of DMF and the mixture is stirred at room temperature for 30 minutes. To the mixture, a solution of 84 mg (0.5 mmol) of bromide in 1 ml of DMF is again added and the mixture is stirred at 5 to 10 ° C for 30 minutes. The mixture is then extracted with 100 ml

  of ethyl acetate. The extract is washed with an aqueous solution of bicarbonate

  sodium bonate, water and saturated NaCl solution successively and dried over MgSO 4. After evaporation to dryness, the oily residue is chromatographed on a column packed with silica gel (Kieselgel 60, 30 g) and eluted with 1% chloroform and methanol in chloroform successively, monitoring by TLC and HPLC. We collect

  the desired fractions eluting with 1% methanol in

  form and evaporate to dryness. The residue is triturated with ether / n-hexane to give 91 mg of the title compound. The crude secondary fractions are ironed in chromatography in the same way, which gives another 63 mg of product. The total yield is therefore 154 mg (57%). Purity estimated at 80% by HPLC. Melting point: 100 ° C (dec). IR: ν max (KBr) in cm 1: 1765, 1670, 1610, 1530, 1380, 1240, 1210, 1180,

1100, 1070, 1040.

  UV: kma (methanol) in nm (c) 233 (17000), 290 (13000).

  NMR: δ (CDCl 3) in ppm: 0.90 (3H, t, I = 7 Hz, CH 2 CH 3); 1.2-1.8 (5H, m, CHCH3 and CH3CH2CH3); 1.8-2.1 (2H, m, = CH-CH2CH2); 2.06 (3H, s, COCH3); 3.43 (2H, br-s, 2-H); 4.05 (3H, s, OCH3); 5.08 (1H, d, I = 4.5 Hz, 6-H); 5, 32 (2H, br-s), NH 2); 5.5-5.7 (1H, m, CH = C); 5.94 (1H, d-d, I = 8 and 4.5 Hz, 7-H); 6.13 (1H, d, I = 11 Hz, 3-CH = C); 6.84 (1H, s, thiazole-H); 6.97, q,

  I = 7 Hz, CH-CH3); 7.48 (1H, d, I = 8 Hz, NH).

  HPLC: retention time 8 minutes (MeOH / phosphate buffer pH 7, 7/3, 1 ml / min.)

EXAMPLE 25

  Diphenylmethyl-7-r [2- (2-tritylaminothiazol-4-yl) -2- (Z) -isopropyloxyimino-

  acetamido] -3 - [(Z) -1 propenyl] -3-cephem-4 carboxylate (VIII, R 2a = CH (CH 3) 2,

R3 = H)

  To a mixture of 2- (2-tritylaminothiazol-4-yl) -2- (Z) -isopropyl-

  oxyiminoacetic acid (III, R2a = CH (CH3) 2: 754 mg, 1.60 mmol) and dichloro

  methane (7 ml), phosphorus pentachloride (332 mg, 1.60 mmol

  1c) at -10 ° C. The mixture is left standing for 20 minutes at the same temperature and is added dropwise to a solution of diphenylmethyl-7-amino-3-r (Z) -1-propenyl hydrochloride. -3-cephem-4-carboxylate (XIII, R3 = H: 443 mg, 1 mmol) and N, O-bis (trimethylsilyl) acetamide (0.74 mL, 4.4 mmol) in dichloromethane (5 mL) at -10 ° C. The reaction mixture is left standing for 30 minutes at the same temperature and poured into ice water. Extraction of the mixture with ethyl acetate followed by evaporation of the extracts under reduced pressure gives the crude product in the form of an oil which is chromatographed on a column packed with sodium hydroxide. silica (eluted with chloroform) to give 419 mg (49%) of VIII (R2 = CH (CH3) 2, R3 = H) as an amorphous powder. IR: ν max (KBr) in cm -1: 1780, 1720, 1680.

  * R. Bucourt et al., Tetrahedron 34, 2233 (1978).

EXAMPLE 26

  7-E2- (2-Aminothiazol-4-yl) -2- (Z) -isopropyloxyiminoacetamidol-3- (Z) - acid

  1-propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH (CH3) 2 R3 = H)

  A mixture of VIII (R 2a = CH (CH 3) 2, R 3 = H: 400 mg, 0.47 mmol

  1c) and 85% formic acid (2ml) for 3 hours at room temperature and hydrochloric acid (0.08ml) is added to the mixture. The mixture is stirred for a further 4 hours and evaporated under reduced pressure. The residue is triturated in the presence of isopropyl ether, which gives the

  crude product which is purified by chromatography on a column containing

  silica gel C-18 (eluent, 30% aqueous MeOH); followed by a concentration under reduced pressure which gives the title compound as needles. Yield 70 mg (33%). Fusion point:

  -175 C (dec.). Estimated purity: 90%.

  IR: ν max (KBr) in cm -1: 1760, 1660, 1540, 1380.

1%

  UV: x (pH 7 phosphate buffer) in nm (Elcm) 232 (370), 284 (357).

max 1cm

44 2583757

  NMR: a (D20 + NaHCO3) in ppm: 1.50 (6H, d, I = 6 Hz, i-Pr); 1.76 (3H, d, I = 6Hz, = CH-CH3); 3.65 (2H, ABq, I = 18 Hz, 2-H); 5.42 (1H, d, I = 4 Hz,

  6-H); 5.80-6.40 (3H, m, vinyl-H, 7-H); 7.15 (1H, s, thiazole-H).

EXAMPLE 27

  Diphenylmethyl-7- [2- (2-tritylaminothiazol-4-yl) -2- (Z) allyloxyiminoacetamido] -3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (2) (VIII, R2a = CH2CH-CH2, R3 = H)

  To a mixture of 2- (2-tritylaminothiazol-4-yl) -2- (Z) -allyloxy acid

  iminoacetic acid (III, R2a = CH2CH = CH2) (750 mg, 1.60 mmol) and dichloromethane

  methane (5 ml), phosphorus pentachloride (332 mg, 1.60 mmol

  at -10 ° C. The mixture is allowed to stand at the same temperature for minutes and added dropwise to a solution of diphenylmethyl-7-amino-3 - [(Z) -1-propenyl] -3-hydrochloride. -ephem-4-carboxylate (XIII, R3 = H: 443 mg, i mmol) and N, O-bis (trimethylsilyl) acetamide (0.74 mL, 4.4 mmol) in dichloromethane (5 mL) A -10 C. The reaction mixture is allowed to stand for 30 minutes at the same temperature and poured into ice water. Extraction of the mixture with chloroform and evaporation of the extracts under reduced pressure gives the crude product as an oil which is chromatographed on a column packed with silica gel (eluted with chloroform), and gives 817 mg (95%) of VIII

  (R2a = CH2CH = CH2, R3 = H) in the form of an amorphous powder.

  IR: 9max (KBr) in cm-1: 1780, 1720, 1680.

  * R. Bucourt et al., Tetrahedron 34, 2233 (1978).

EXAMPLE 28

  7- [2- (2-Aminothiazol-4-yl) -2- (Z) -alloxyiminoacetamido] -3 - [(Z) -1-) acid

  propenyl-3-cephem-4-carboxylic acid (Ia, R 2 = CH 2 CH = CH, R 3 = H) A mixture of VIII (R 2a = CH 2 CH = CH 2 RH: 810 mg, 0.95 mole) and A formic acid is stirred. 85% (2 ml) for 3 hours at room temperature and hydrochloric acid (0.1 ml) is added to the mixture. The mixture is stirred for 3 hours and evaporated under reduced pressure. Trituration of the residue in the presence of isopropyl ether gives the crude product which is dissolved in a small amount of methanol and chromatographed on a column packed with C-18 silica gel (eluted with 30% aqueous MeOH). The eluate is concentrated under reduced pressure and lyophilized to give 215 mg (50%) of the title compound as

  an amorphous powder. Melting point: 140 ° C (dec). Estimated purity: 80%.

  IR: ν max (KBr) cm -1: 1770, 1660, 1620.

  UV: Xmax (pH 7 phosphate buffer) in nm (EI,%) 232 (378), 285 (326c.

  NMR: 6 (D20 + NaHCO3) in ppm: 1.78 (3H, d, I = 6 Hz, C = CH-CH3); 3.62 (2H, ABq, I = 18 Hz, 2-H); 5.50-6.30 (7H, m, vinyl-H, 6.7-H); 7.18 (1H, s, thiazole-H).

EXAMPLE 29

  7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (Z) -ethoxyiminoacetamido] -3-E (Z) 1 -propenyl) -3-cephem-4-carboxylic acid (Ia, R2 = C2H5, R3 = H)

  To a solution of (Z) -2- (2-N-tritylaminothiazol-4-yl) -2-ethoxy-

  iminoacetic acid (III, R2a = C2H5) (458 mg, 1.0 mmol) and 1-hydroxybenzoate

  triazole (135 mg, 1.0 mmol) in a mixture of dichloromethane (20 ml) and

  tetrahydrofuran (7 ml) at room temperature, add dicyclo

  Clohexylcarbodiimide (210 mg, 1.0 mmol), the mixture is stirred for minutes, filtered and the filtrate is concentrated to dryness. The residue is dissolved in tetrahydrofuran (10 ml) and diphenylmethyl-3-propenyl-3-cephem-4-carboxylate hydrochloride (XIII, R3 = H, 443 mg, 1 mmol) and sodium bicarbonate are added. (84 mg, 1 mmol). Water (10 drops) is added and the resulting solution is stirred at room temperature for 12 hours. The reaction mixture is diluted with ether and filtered. The filtrate is concentrated to give an oil. This oil is chromatographed on silica gel (230 to 400 mesh), eluted with hexane / ethyl acetate 2/1 to give the acylation product (VIII, R2a = C2H5, R3 = H ) (400 mg). It is dissolved in formic acid (1.6 ml), stirred vigorously for 60 minutes and 12N HCl (50 μl) is added. The mixture is stirred at room temperature for 3 hours, diluted with water (2 ml) and toluene (20 ml) and

  evaporates at 30 C to dryness. The residue is triturated in the presence of isopropyl

  ether, the resulting precipitates are collected and washed with

  isopropyl ether. The product is chromatographed on silica gel.

  this C-18 eluting with 3/7 methanol / water to give the title compound as an amorphous solid, 100 mg (23%). Point of

  merger: 158 C (dec). Estimated purity: 90% (based on HPLC).

  IR: V max (KBr) cm -1: 3600-2600, 1765, 1660, 1620, 1530, 1385, 1355, 1035.

  UV: xmax (MeOH) in nm (e) 235 (16100), 286 (13800).

  NMR: a (D20 + NaHCO3) in ppm: 1.45 (3H, t, I = 7 Hz); 1.77 (3H, d, I = 6 Hz); 3.45 and 3.75 (2H, ABq, I = 18 Hz); 4.40 (2H, q, I = 7 Hz); 5.40

  (1H, d, I = 5 Hz); 5.76 - 6.20 (3H, m); 7.13 (1H, s).

  * R. Bucourt et al., Tetrahedron 34, 2233 (1978).

46 2583757

EXAMPLE 30

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-cyclopropylmethoxyiminoacetamido] acid

  3 - [(Z) -1) propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = CH2- <, R3 = H)

  To a solution of (Z) -2- (2-N-tritylaminothiazol-4-yl) -2-cyclopropanic acid

  propylmethyliminoacetic (III, R2a = CH2-4) (484 mg, 1.0 mmol) and

  1-hydroxybenzotriazole (135 mg, 1.0 mmol) in a mixture of dichloromethane

  methane (20 ml) and tetrahydrofuran (7 ml) at room temperature, dicyclohexylcarbodiimide (210 mg, 1.0 mmol) was added. We shake the

  After 80 minutes, the mixture is filtered and the filtrate is concentrated to dryness.

  The residue is dissolved in tetrahydrofuran (10 ml) and diphenylmethyl-3-propanyl-3-cephem-4-carboxylate hydrochloride (XIII,

  R3 = H) (443 mg, 1.0 mmol) and sodium bicarbonate (84 mg, 1.0 mmol).

  Water (10 drops) is added and the resulting solution is stirred at room temperature for 12 hours. The reaction mixture is diluted with ether and filtered. The filtrate is concentrated to give an oil. We

  This oil is chromatographed on silica gel (230-400 mesh).

  The mixture is eluted with hexane / ethyl acetate 2/1 to give the acylation product (VIII, R2a = CH2-, R3 = H) (500 mg). It is dissolved in formic acid (2.0 ml, stirred vigorously for 60 minutes at room temperature and 12N HCl (50 μl) is added.The mixture is stirred at room temperature for 3 hours. diluted with water (2 ml) and toluene (20 ml) and evaporated to dryness to 30 ° C. The mixture is triturated in the presence of isopropyl ether and the resulting precipitates are collected and washed with water. isopropyl ether.

  chromatography on silica gel C-18 eluting with a methacrylate mixture

  water / 4/6 to give the title compound as an amorphous solid, 80 mg (19%). Melting point: 150 C (dec). Estimated purity: 85%

(based on HPLC).

  IR: ν max (KBr) in cm -1: 3600-2600, 1765, 1660, 1620, 1530, 1350, 1025,

1010.

  UV: X max (MeOH) in nm (i) 236 (17200), 286 (14400).

  NMR: 6 (D20 + NaHCO3) in ppm: 0.25-0.85 (4H, m); 1.20-1.60 (1H, m); 1.75 (3H, d, I = 6 Hz); 3.45 and 3.75 (2H, ABq, I = 18 Hz); 4.17 (2H, d,

  I = 7 Hz); 5.40 (1H, d, I = 5 Hz); 5.75 - 6.20 (3H, m); 7.14 (1H, s).

  * Glaxo, Japan Kokai 59-106492 (6/20/84).

EXAMPLE 31

  Diphenylmethyl-7- [2- (2-tritylaminothiazol-4-yl) -2- (propargyloxyimino-

  acetamido] -3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (VIII, R2a = CH2COH,

R = H)

  To a cooled solution of 750 mg (1.65 mmol) of diphenylmethyl-7-amino-3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate hydrochloride (XIII, R3 = H) and 1 05 ml (5 mmol) of N, O-bis (trimethylsilyl) acetamide in 17 ml of dry methylene chloride, a solution of 750 mg is added.

  (1.65 mmol) 2-tritylaminothiazol-4-yl-2- (2-propargyloxyimino) acid

  acetic acid (III, R2a = CH2C = OH) and 415 mg (2.0 mmol) of phosphorus pentachioride in 17 ml of dry methylene chloride and the mixture is stirred for 1 hour at room temperature. The reaction mixture is poured into aqueous NaHCO3 solution (30 ml) and diluted with 60 ml of ethyl acetate. The organic layer is washed with water (30 ml x 2) and brine (20 ml), dried over MgSO 4 and concentrated under reduced pressure. The oily residue is chromatographed on a column packed with silica gel (Waco gel 200, 20 g) and eluted with CHCl3. Fractions containing the desired product are pooled and concentrated under reduced pressure.

  gives 90.5 mg (97%) of the title compound. Melting point: 155 C (dec.).

  IR: V max (KBr) in cm -1: 3280, 2120, 1780, 1720, 1670.

* U.S.P. 4,294,960 (10/13/81).

EXAMPLE 32

  7-E (Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxyiminoacetamido) - acid

  3-E (Z) -1-propenyl] -3-cephem-4-carboxylic acid (Ia, R = CH 2 C = OH, R 3 = H) A solution of 900 mg (1.18 g) is stirred at room temperature for 1 hour. mmol) of VIII (R2a '= CH2CECH, R3 = H) in 3 ml of 85% formic acid. To the reaction mixture, 0.3 ml of concentrated HCl was added and the suspension was stirred for 4 hours at room temperature. The mixture is filtered and washed with a small portion of formic acid and concentrated under reduced pressure. The residue is chromatographed on a column packed with reverse phase silica gel from a cartridge of PrepPAK-500 / C18 (Waters). The column is eluted with water and with a 30% water / MeOH mixture successively. Fractions containing the desired product are pooled and lyophilized to give 105 mg (22%) of the compound.

in heading.

  IR: ν max (KBr) cm -1: 3400, 3280, 1770, 1670, 1630.

  UV: Xmax (pH 7 phosphate buffer) in nm (c) 229 (17000), 285 (14200).

  NMR: 6 (D20 + NaHCO3) in ppm: 1.75 (3H, d, I = 6 Hz, CH = CH-CH3); 3.61 (2H, ABq, 2-H); 4.98 (2H, s, O-CH2-CECH); 5.39 (1H, d, I = 5 Hz, 6-H); 5.80 (1H, m, OH = CH-CH3); 5.91 (1H, d, I = 5 Hz, 7-H); 6.08 (1H, d, I = 11 Hz,

  CH = CHCH 3); 7.22 (1H, s, thiazole-5H).

EXAMPLE 33

  Diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -2- (trityloxyimino-

  acetamido)] - 3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (VIII, R 2a = Tr,

R3 = H)

  To a mixture of 2- (2-tritylaminothiazol-4-yl) -2- (Z) -trityloxy acid

  iminoacetic acid (III, R2a = Tr) (873 mg, 1.30 mmol) and dichloromethane (5 ml), phosphorus pentachloride (297 mg, 1.43 mmol) was added at 5 ° C. The mixture was allowed to stand for 20 minutes at the same temperature

  and added dropwise to a solution of diphenyl hydrochloride

  methyl-7-amino-3- (1-propenyl) -3-cephem-4-carboxylate (XIII, R3 = H: 443 mg, 1 mmol) and N, O-bis (trimethylsilyl) acetamide (0.74 ml) 4.4 mmol) in dichloromethane (5 ml) at -5 ° C. The reaction mixture is allowed to stand for 20 minutes at the same temperature and poured into ice water. Extraction of the mixture with ethyl acetate and evaporation of the extracts under reduced pressure gives the crude product as an oil and is chromatographed on a silica gel column (eluted with chloroform). which gives the title compound under the

  form of an amorphous powder. Yield 510 mg (48%).

  IR: ν max (nujol) in cm 1 1780, 1720, 1680.

  * R. Bucourt et al., Tetrahedron 34, 2233 (1978).

EXAMPLE 34

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-hydroxyilminoacetamido)] - 3 - [(Z) -1) acid

  propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = R3 = R4 = H) A mixture of VIII is stirred for 1 hour at room temperature

  (R2a = Tr, R3 = H) (810 mg, 0.76 mmol) and 85% formic acid (2 ml).

  Hydrochloric acid (0.1 ml) is added to the reaction mixture. The mixture is stirred for 2 hours and evaporated under reduced pressure, the residue is triturated in the presence of isopropyl ether to give the crude product which is chromatographed on a column packed with silica gel C-18 (eluted with 20% aqueous MeOH). The eluate is concentrated under reduced pressure and lyophilized to give the title compound as an amorphous powder. Yield 109 g (35%). Fusion point:

49 2583? 57

 C (dec.). Estimated purity: 75%.

  IR: ν max (KBr) cm -1: 1770, 1760, 1630.

  UV: Xmax (phosphate buffer pH 7) in nm (Elcm) 225 (450), 282 (370).

  NMR: s (D20 + NaHCO3) in ppm: 1.78 (3H, d, I = 6 Hz, CH = CH-CH3); 3.64 (2H, ABq, I = 18 Hz, 2-H); 5.40 (1H, d, I = 4 Hz, 6-H); 5.70-6.25 (3H, m, 7-H,

vinyl-H); 7.14 (1H, d, thiazole-H).

EXAMPLE 35

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido) j] -

  3-r (Z) -1-propenyl-3-cephem-4-carboxylate (Ib, R2 = R3 = H, R4 AX) to an ice-cooled and stirred solution of Ia (R2 = R3 = H, Example 34); (270 mg, 0.66 mmol) in dry DMF (2 mL) was added sodium carbonate (105 mg, 0.99 mmol) and a bromide solution.

  1-acetoxyethyl (397 mg, 2.38 mmol) in DMF (0.6 ml) in three parts;

  15 minutes apart. The reaction is monitored by TLC (Merck Kieselgel 60F254, MeCN / H2O 10/1). The mixture is stirred for a further 30 minutes and three major spots are revealed at Rf 0.11, 0.58 and 0.75. After dilution with ethyl acetate (50 ml), the resulting precipitate is filtered off and the filtrate is washed with water (three times) and then with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in a small amount of chloroform. The solution is chromatographed on a column packed with Kieselgel 60 (20 g) and eluted with CHCl3 and then with a 1/20 mixture of MeOH and CHCl3. Fractions revealing a spot at Rf 0.58 per TLC are pooled and concentrated to a small volume. To the concentrate, isopropyl ether is added to give a precipitate which is collected by filtration and gives 61 mg (19%) of

  the desired acetoxyethyl ester. Melting point: 120-125 C. Estimated purity

MW: 75% by HPLC.

  IR: mnax (KBr) cm -1: 1765, 1665, 1610, 1530, 1375.

  UV:> nax (EtOH) in nm (s) 223 (19000), 264 (12000), 285 (12000).

NMR: δ (CDCl 3) in ppm: 1.50 (EH, d, I = 5.0 Hz, CHCH 3); 1.65 (3H, d, I = 6.0 Hz, = CHCH3); 2.07 (3H, s, COCH3); 3.45 (2H, br, SCH2); 5.08 (1H, d, I = 5.5 Hz, 6-H); 5.5-6.0 (2H, m, 7-H and = CH); 6.15 (1H, d, I = 10 Hz,

  3-CH =); 6.96 (2H, m, thiazole-H and OCHCH3).

  * packing: gel TSK 120 T (4 x 250 mm)

  Mobile phase: CH3CN / phosphate buffer pH 6 (2/3).

EXAMPLE 36

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacétamido)] -

  3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = Ac, R3 = H, R4 = AX) To a stirred mixture of Ia (R = R3 = H) (200 mg 0.49 mmol) and K 2 CO 3 (34 mg, 0.24 mmol) in dry DMF (5 ml) is added at 0 ° C. a solution of 1-acetoxyethyl bromide (81 mg, 0.49 mmol) in dry DMF (0.1 mmol). Potassium carbonate and bromide are added to the mixture four more times at 45 minute intervals. We monitor the

  reaction mixture by HPLC (Lichrosorb RP-18 4 x 300 mm, 4/1 MeOH / H 2 O).

  After the addition, the mixture is stirred for 30 minutes. The reaction mixture showing a major peak at 4.5 minutes (retention time) is diluted with AcOEt (40 ml), washed with water (three times) and a saturated solution.

  NaCl, dried over MgSO4 and evaporated to a small volume. We pass the concentration

  in column chromatography packed with Kieselgel 60 (8 g) and eluted with 1/20 MeOH / CHCl3. The eluate is monitored by HPLC and the fractions which peak retention time are pooled at 4.5 minutes and concentrated to about 2 ml. To the concentrate was added isopropyl ether (20 ml) to give 190 mg (72%) of the title compound.

  in its solvate form in isopropyl ether. Estimated purity: 85%.

  IR: ν max (KBr) cm -1: 3280 (w), 1770 (s), 1680 (m), 1540 (m), 1215 (s).

  UV: x max (MeOH) in nm (c) 231 (17600), 293 (9800).

  NMR: δ (CDCl 3 + D 2 O) in ppm: 1.5 (3H, d, I = 6 Hz, OCHCH 3); 1.65 (3H, d-d, I = 7 and 1 Hz, = CHCH3); 2.05 (3H, s, COCH3); 2.2 (3H, s, COCH3); 3.44 (2H, br, SCH2); 5.1 (1H, d, I = 5 Hz, 6-H); 5.5-6.0 (1H, m, 3-CH = CH); 5.9 (1H, d, I = 5 Hz, 7-H); 6.15 (1H, d, I = 11 Hz, 3-CH = CH); 6.89 (1H, m, OCHCH3);

6.93 (1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C21H23N508S2.4 / 5 [(CH3) 2CH] 20

  and the following values are obtained:

C H N S

  - calculated .......... 50.04 5.57 11.31 10.35 - found ............... 49.78 5.47 10.90 10.28

EXAMPLE 37

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2- (acetyloxyiminoacetamido)] - 3 - [(Z)] acid

  1-propenyl] -3-cephem-4-carboxylic acid (Ia, R3 = Ac, R3 = H)

  A suspension of 200 mg (1.30 mmol) of 1-hydroxy-1H-monohydrate

  benzotriazole, 631 g (1.30 mmol) of 2- (2-tritylaminothiazol-4-yl) -

  2-acetoxyiminoacetic acid and 268 mg (1.30 mmol) of dicyclohexylcarbodiimide

51 2583757

  The mixture is stirred for 1 hour at 5 ° C. To the mixture is added 510 mg (1.26 mmol) of diphenylmethyl-7-amino-3- [r (Z) -1-propylmyl] -3-cephem-4-carboxylate. The mixture is stirred for 5 hours at room temperature and diluted with 50 ml of AcOEt. The reaction mixture is washed with 1N HCl (25 ml), water (25 ml) and brine (25 ml). It is dried over MgSO 4 and concentrated under reduced pressure. The residue is chromatographed on a column packed with silica gel (30 g) and eluted with toluene / AcOEt (10/1). The fractions which reveal a spot at Rf 0.20 per TLC (toluene / AcOEt 10/1) are combined and evaporated under vacuum. The residual oil (about 1.15 g) is dissolved in a mixture of 8 ml of% TFA and 2 ml of anisole and the mixture is stirred for 1 hour in an ice bath. The solution was concentrated under reduced pressure and triturated in the presence of isopropylether (40 ml) and n-hexane (10 ml) to give 432 mg of crude product which was purified by column Bondapak C-18 eluted with 30% aqueous MeOH. Fractions with a peak retention time of 6.9 minutes (HPLC) are pooled,

  concentrated and lyophilized to give 153 mg (27%) of the compound

  only in the form of amorphous powder. Melting point: 155 C (dec.). Estimated purity: 65%. HPLC (Lichrosorb RP-18 4 x 300 mm, MeOH / pH 7 3/7 buffer);

retention time 6.9 minutes.

  IR: ν max (KBr) in cm -1: 3260, 1775, 1765, 1665.

  UV: kmax (EtOH) in nm (e) 230 (20100), 292 (12700).

  NMR: a (DMSO-d6) in ppm: 1.63 (3H, dd, I = 1 and 7 Hz, = CHCH3); 2.16 (3H, s, OAc); 3.55 (br s, 2H, 2-H); 5.22 (1H, d, I = 5 Hz, 6-H); 5.70 (1H, m, = CHCH3); 5.76 (1H, dd, I = 5 and 8 Hz, 7-H); 6.10 (1H, d, I = 11 Hz, 3CH = CH-); 7.05 (1H, s, thiazole-H); 7.28 (2H, s, -NH 2); 9.80 (1H, d,

I = 8 Hz).

  * Japan Kokai 59-184186 (10/18/84, Meiji Seika).

EXAMPLE 38

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-acétoxyiminoacétamido] -

  3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = Ac, R3 = H. R4 = AX) To a solution of 20 mg (0.05 mmol) of Ia (R2 = Ac, R3 = H) in 0.2 ml of dry DMF, 6 mg (0.05 mmol) of K2CO3 are added and the mixture is stirred for 5 minutes at 5 ° C. 1-acetoxyethyl bromide (10 til) to the mixture and the suspension is stirred for 1 hour at the same temperature. The reaction mixture is diluted with 5 ml of AcOEt, washed successively with water (2 ml x 3) and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is triturated in the presence of 10 ml of isopropyl ether to give the desired acetoxyethyl ester which is filtered off and dried. Yield 15 mg (63%). The spectral data of the product are consistent with those of the

  compound prepared in Example 36.

EXAMPLE 39

  Pivaloyloxymethyl-7-r (Z) -2- (2-aminothiazol-4-yl) -2-hydroxytminoacétamido] -

  3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = R3 = H, R4: PV) A stirred mixture of 1b (R2 = R3 = H) (200 mg, 0, 49mmol) and Na2CO3 (26mg, 0.24mmol) in dry dimethylacetamide (5ml) was added at -50C pivaloyloxymethyl iodide (118mg, 0.49mmol) and the mixture was shaken. mix for 45 minutes. Sodium carbonate (13 mg, 0.12 mmol) and iodide (59 mg, 0.12 mmol) are added again to the mixture and the mixture is stirred at the same temperature. After 30 minutes, the mixture with spots at Rf 0.60 (major) and 0.70 (minor) and 0.80 (minor) by TLC (Merck Kieselgel 60 F254, MeCN-H20 20/1) is diluted with ethyl acetate (25 ml) and the solution is washed with water (three times) and

  saturated NaCl solution, dried over MgSO 4 and evaporated to dryness.

  The residue is dissolved in a small amount of CHCl 3 and passed over a column packed with Kieselgel 60 (13 g), washed with CHCl 3 (50 ml) and eluted with 1/20 MeOH-CHCl 3 ( 150 ml). The fractions giving a spot at Rf 0.60 in TLC are pooled and evaporated. The residue is dissolved in benzene and the solution is lyophilized to give 63 mg (25%) of the title compound. Melting point: 101-1040C. Estimated purity:%. HPLC (Develosil 4 x 100 mm, MeCN / phosphate buffer pH 7 3/2),

retention time 4.6 minutes.

  IR: νmax (KBr) in cm-1: 1780, 1755, 1670, 1530, 1120.

  UV: X max (MeOH) in nm (E) 270 (12000).

  NMR: s (CDCl3 + D2O) in ppm: 1.22 (9H, s, 3 x CH3); 1.56 (3H, dd, I = 1 and 7 Hz,: CHCH3); 3.45 (2H, m, S-CH 2); 5.11 (1H, d, I = 4 Hz, 6-H); 5.5-5.95 (4H, n1: C, CHCH3 and OCH2O); 6.14 (1H, d, I = 11Hz, 3-CH =); 7.02 (1H, s, thiazol-H).

EXAMPLE 40

  Acetoxymethyl-7-r (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacétamidoj-

  3-r (Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = R3 = H, R4 = AM *) to an agitated suspension of (R2 = R3 = H) (280 mg, 0.68 mmoleY and Na2CO3 (36 mg, 0.34 mmol) in dry DMF (5 mL) was added at -10 C in minutes a solution of acetoxymethyl bromide in dry DMF (104 mg, 0, 68 mmol / 100 μl) After 30 minutes, a supplement of Na 2 CO 3 is added.

53 2583757

  (18 mg, 0.17 mmol) and the bromide solution (52 mg, 0.34 mmol / 50 μl) in small portions over 10 minutes. The mixture is stirred at the same temperature for 30 minutes. The reaction mixture which gives four spots at Rf 0.10 (BMY-28232), 0.15, 0.60 and 0.75 per TLC (Merck Kieselgel 60 F254, MeCN-H20 10/1) is diluted with AcOEt ( 25 ml), washed with water (three times) and saturated NaCl solution, dried over MgSO 4 and evaporated. The residue is dissolved in a small amount of CHCl 3 and loaded on a column packed with Kieselgel 60 (18 g) which is washed with CHCl 3 (50 ml) and eluted with MeOH / CHCl 3 (1 / 20, 250 ml). We collect the

  fractions which give a spot at Rf 0.60 per TLC and evaporated under vacuum.

  The residue was dissolved in benzene and lyophilized to give 45 mg (14%) of the title compound. Melting point: 107-110 C. Estimated purity:

  %. HPLC (Lichrosorb 4 x 300 mm, MeCN / H 2 O 2/3), retention time 6.0

utes.

  IR: ν max (KBr) in cm -1: 1770, 1665, 1530, 1370, 1200, 1000, 985.

  UV: X max (MeOH) in nm (δ) 268 (10900).

  NMR: δ (CDCl3 + O20) in ppm: 1.65 (3H, s, I = 7 Hz, -CHCH3); 2.1 (3H, s, COCH3); 3.43 (2H, br, SCH2); 5.1 (1H, d, I = 5 Hz, 6-H); 5.3-5.95 (4H, m, 7-H, = CHCH 3 and OCH 2 O); 6.15 (1H, d, I = 11 Hz, 3-CH =); 6.96 (1H, s,

thiazole-H).

* AM = -CH20COCH3

EXAMPLE 41

  Diphenylmethyl-7-amino-3 - [(E) -1-butenyl] -3-cephem-4- hydrochloride

  carboxylate (XIII (E), R3 = CH3, R4a = CHPh2)

  A mixture of diphenylmethyl-7-amino-3 - [(E) -1- hydrochloride

  butenyl] -3-cephem-4-carboxylate (from Example 6) (2.9 g, 6.5 mmol)

  1a) and benzophenone (1.2g, 6.5mmol) in methanol (300ml) is irradiated with a low pressure mercury lamp (2537 Angstroms, 6W) at room temperature. for 26 hours. The solvent is evaporated

  under vacuum and the residue is dissolved in chloroform. The solution is treated

  with carbon and filtered. The filtrate is diluted with ether, which precipitates 2.2 g (76%) of the title compound, the contaminated isomer E by% of the Z isomer which is used for the next step without further purification. .

  IR: V max (KBr) cm -1: 1780, 1720, 1625.

  UV: Amax (MeOH) in nm (c) 298 (10200).

  NMR: δ (DMSO-d6) in ppm: 0.97 (3H, t, I = 7 Hz, CH3); 2.15 (2H, m, CH 2 CH 3); 3.84 (2H, br-s, 2-H); 5.15 (1H, d, I = 5 Hz, 6-H); 5.30 (1H, d, I = 5 Hz, 7-H); 6.65 (1H, d, I = 16 Hz, 3-CH =); 6.97 (1H, s, OCH); 7.45 (1OH, s, phenyl-H). HPLC: Lichrosorb RP-18 (4 x 250 mm), CH3CN / phosphate buffer pH 7, 3/2,

  2 ml / min. Retention time: Z isomer 5.1 minutes, E isomer 6.7 minutes.

EXAMPLE 42

  Diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(E) -1-butenyl] -3-cephem-4-carboxylate (XIV (E), R 2 = R 3 = CH 3, R 4a = CHPh 2)

  A suspension of diphenylmethyl-7-amino-3 - [(E) -1-

  Crude butenyl-3-cephem-4-carboxylate (1.97 g, 4.3 mmol) in AcOEt (30 mL) is shaken in the presence of NaHCO3 to give a clear two-layer solution. The organic layer is separated, washed with water and then with saturated aqueous NaCl solution, dried over MgSO 4 and concentrated in vacuo. The residue is redissolved in DMF (20 ml). To the solution was added 1 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetoxy] benzotriazole (2.07 g, 6.5 mmol). The mixture is stirred at room temperature for 1 hour and dissolved with AcOEt (100 ml). The diluted solution is washed with aqueous NaHCO3, water and aqueous NaCl successively, dried over MgSO4 and evaporated in vacuo. The residue is chromatographed on a column packed with silica gel (50 g) and eluted with toluene / ethyl acetate 2/1 to give 1.58 g (61%) of the title compound.

  IR: Vmax (KBr) in cm-1: 1770, 1720, 1670.

  UV: Xmax (MeOH) in nm ({) 297 (18800).

  NMR: δ (CDCl 3 + D 2 O) in ppm: 0.97 (3H, t, 1 = 7 Hz, CH 3); 2.12 (2H, m, CH 2 CH 3); 3.52 (2H, s, 2-H); 4.00 (3H, s, OCH3); 5.10 (1H, d, I = 4.5 Hz, 6-H); 5.93 (1H, d, I = 4.5 Hz, 7-H); 5.7-6.3 (1H, m, = CH-CH 2); 6.74 (1H, s,

  thiazole-H); 6.96 (1H, s, OCH); 7.25 (10H, s, phenyl-H).

EXAMPLE 43

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-E (E) -1-butenyl] -3-cephem-4-carboxylic acid (Ia (E), R = R3 CH3)

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-

  methoxyiminoacetamido] -3 - [(E) -1-butenyl] -3-cephem-4-carboxylate (650 ng,

  1.1 mmol), TFA (3 ml) and anisole (1 ml) are stirred at 5 ° C. for 30 minutes.

  and diluted with isopropyl ether. The resulting precipitate is collected by filtration. It is dissolved in formic acid and passed

  in chromatography on a column containing a lining (100 ml) from

  PrepPAK cartridge (Waters) was washed with water and then eluted with 30% methanol. The eluate was monitored by HPLC and the desired fractions pooled, concentrated and lyophilized to give 277 mg (59%) of the title compound. Melting point:> 170 C (Dec. prog.). Purity

estimated: 90%.

IR: ν max (KBr) cm -1: 1770, 1660.

  UV: λ max (pH 7 phosphate buffer) in nm (c) 232 (15700), 292 (22400).

  NMR: 6 (D20 + NaHCO3) in ppm: 1.18 (3H, t, I = 7Hz, CH2CH3); 2.30 (2H, m, CCH 2 CH 3); 3.83 (2H, s, 2-H); 4.15 (3H, s, OCH3); 5.37 (1H, d, I = 5 Hz, 6-H); 5.92 (1H, d, I = 5 Hz, 7-H); 5.9-6.4 (1H, m, = CHCH2); 5.66 (1H, d,

  I = 16 Hz, 3-CH =); 7.18 (1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C17H19N505S2. 1 / 2:20

  and the following values are obtained:

C H N S

  - calculated .......... 45.73 4.51 15.69 14.36 - found ........... 45.63 4.28 15.33 14.27 * 3-trans-butenyl-cephalosporin Ia (E, R2 = R3 = CH3) which is

  identical to that described in Example 15.

EXAMPLE 44

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3-E (E) -1-butenyl] -3-cephem-4-carboxylate (Ib (E), R2 = R3 = CH3, R4 = AX) A mixture of Ia (E) (R = R = CH3 (438 mg, 1 mmol) and K2CO3 (207 mg, 1.5 moles) in DMF (10 mL) is treated with acetoxyethyl bromide (250 mg, 1.5 mmol) by a procedure similar to that described in Example 16, yielding 350 mg (67%) of the ester AX

  desired, which is identical to that of Example 16. Melting point: 110-

 C. Estimated purity: 90% by HPLC.

  IR: V max (KBr) in cm -1: 1760 (br.), 1670, 1610.

  UV: X max (MeOH) in nm (c) 232 (16600), 298 (19300).

  NMR: δ (CDCl 3) in ppm: 1.05 (3H, t, 1 = 7Hz, CH 2 CH 3); 1.54 (3H, d, I = 6Hz, CHCH3); 2.08 (3H, s, COCH3); 2.0-2.4 (2H, m, -CH 2 CH 3); 3.57 (2H, s, 2H); 4.05 (3H, s, OCH3); 5.07 (1H, d, I = 5 Hz, 6-H); 5.8-6.3 (2H, m,

  7-H and = CHCH 2 -); 6.86 (1H, s, thiazole-H); 6.8-7.1 (2H, m, OCH and 3-CH =).

  On analysis, it is found that the product obtained has the formula;

C21H25N507S2. 1/4 [(CH3) 2CH] 20

  and the following values are obtained:

C H N S

  - calculated .......... 49.21 5.23 12.75 11.68 - found ............... 49.44 5.28 12.24 11.70

EXAMPLE 45

  7-amino-3 - [(E) -1-propenyl] -3-cephem-4-carboxylic acid (XIII (E), R = R4a = H)

  A solution of 7-amino-3 - [(Z) -1-propenyl] -3-cephem-4- acid

  carboxylic acid (1.2 g, 5 mmol) and benzophenone (900 mg, 5 mmol) in methanol (800 ml) containing 1 ml of 6N hydrochloric acid is irradiated with a low pressure Hg lamp (2 537 angstroms, 6 W) at room temperature for 44 hours. The reaction mixture is evaporated to dryness and the residue is distributed in a mixture of 0.15N HCl (200 ml) and ether (200 ml). The aqueous layer is separated, treated with activated charcoal and filtered. The filtrate is adjusted to pH 3 with dilute NaOH solution and cooled to give a precipitate. It was collected by filtration and washed with water and acetone to give 476 mg of the title compound E isomer, m.p. 245C (dec.prog.). The second collection (195 mg) is obtained by concentration of the filtrate at 30 ml. yield

  total 671 mg (56%). The product contains less than 5% of the corresponding Z isomer

laying.

  IR: ν max (KBr) in cm 1: 1800, 1620, 1540, 1420, 1360.

  UV: Xmax (pH 7 phosphate buffer) in nm ({) 292 (15000).

  NMR: 6 (D 2 O + Na 2 CO 3) in ppm: 1.78 (3H, d, I = 6 Hz, = CH-CH 3); 3.62 (2H, s, 2-H); 5.03 (1H, d, I = 4.5 Hz, 6-H); 5.3-6.2 (2H, m, = CH and 7-H); 6.52 (1H,

d, I = 16 Hz, 3-CH = C).

  On analysis, we see that the product obtained has the formula:

C10H12N203S.1 / 2:20

  and the following values are obtained:

C H N S

  - calculated .......... 48,18 5,25 11,24 12,86 - found ........... 47,88 4,83 10,79 12,83 * A 4/1 mixture of Z and E isomers

EXAMPLE 46

  7-E (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(E) -1-) acid

  propenyl] -3-cephem-4-carboxylic acid (Ia (E), R2 = CH3, R3 = H) to a stirred solution of 7-amino-3-trans-propenyl derivatives XIII (E, R3 = R4a = H) (720 mg, 3 mmol) and sodium bicarbonate (504 mg,

  6 mmol) in 50% DMF (60 ml) was added 1-E (Z) -2- (2-aminothiazole).

  4-yl) -2-methoxyiminoacetoxy] benzotriazole (954 mg, 3 mmol) and the mixture is stirred for 30 minutes. Add in four portions at 30 minutes

  a further amount of the active ester (1.81 g, 6 mmol).

  The mixture is stirred for a further 2 hours at room temperature and passed over a column packed with a liner from a PrepPAK C-18 cartridge (300 ml, Waters). The column is washed with water and then eluted successively with 10% methanol and 20% methanol. The 20% methanol eluate fractions which peak at the 5.57 minute retention time by HPLC are collected and evaporated to dryness. The residue is dissolved in methanol and filtered. The filtrate is concentrated to 5 ml and the residue is triturated in the presence of an ether / isopropyl ether mixture to give 805 mg (63%) of the title compound.

  melting at 180 ° C. (dec., prog.), purity: 80% by HPLC.

  IR: νmax (KBr) cm -1: 1770, 1670, 1630, 1540, 1380, 1040.

  UV: Xmax (MeOH) in nm (c) 223 (17000), 293 (20000).

  NMR: 6 (D 2 O + Na 2 CO 3) in ppm: 1.93 (3H, d-d, I = 6 and 1.5 Hz, = CH-CH 3); 3.76 (2H, s, 2-H); 4.12 (3H, s, OCH3); 5.32 (1H, d, I = 4.5 Hz, 6-H); 5.86 (1H, d, I = 4.5 Hz, 7-H); 5.8-6.3 (1H, m, = CH-CH3); 6.61 (1H, d-d, I = 16

  and 1.5 Hz, CH = C); 7.13 (1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C16H17N505S2

  and the following values are obtained:

C H N S

  - calculated .... 45.39 4.05 16.54 15.14 - found ..... 45.57-45.41 4.37-4, 29 15.94-15.76 13.90- 13.62 * packing: Lichrosorb RP-18 (4 x 300 mm), mobile phase: MeOH / buffer

at pH 7 (35/65).

EXAMPLE 47

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(E) -1-propenyl] -3-cephem-4-carboxylate (Ib (E), R = CH3, R = H,

R = AX)

  To a stirred mixture of 317 mg (0.75 mmol) trans-propenyl-

  cephalosporin Ia (E, R2 = CH3, R3 = H) and 104 mg (0.75 mmol) of potassium carbonate in 5 ml of DMF, a solution of 167 mg (1 mmol) of bromide is added at 0-5 ° C. of 1-acetoxyethyl in 0.5 ml of DMF and the mixture is stirred at 5 ° C. for 15 minutes. To complete the reaction, a further amount of potassium carbonate (204 mg, 1.5 mmol) and bromide solution in DMF (334 mg, 2 mmol / sec) were added in two portions over a period of 15 minutes each. 1 ml). The mixture is stirred at 5 ° C.

  for another 30 minutes and diluted with 150 ml of ethyl acetate.

  The diluted solution is washed with water and aqueous NaCl, dried in the presence of MgSO 4 and concentrated to dryness. The oily residue is dissolved in a small volume of CHCl 3 and chromatographed on a column packed with silica gel (Merck Kieselgel 60, 40 g), washed with chloroform and eluted with chloroform / methanol (50 / ml). 1). The desired fractions which have a spot at Rf 0.40 are collected by TLC (silica gel, chloroform / methanol 10/1) and a peak at the retention time of 7.7 minutes by HPLC (acetonitrile / buffer pH 7, 1/1) and evaporated to dryness to give an oily residue which is triturated in the presence of a mixture of ether and isopropyl ether to give 270 mg of the ester

  searched heading melting at 140 C (dec.). Estimated purity: 80% by HPLC.

  IR: V max (KBr) in cm -1: 1770, 1670, 1620, 1540, 1380, 1210, 1100, 1070, 1040.

  UV: λmax (MeOH) in nm (c) 234 (17000), 197 (19000).

  NMR: δ (CDCl 3) in ppm: 1.53 (3H, d, I = 5 Hz, C-CH 3); 1.86 (3H, d, I = 6Hz, CH = CH-CH3); 2.08 (3H, s, OCOCH3); 3.55 (2H, br-s, 2-H); 4.05 (3H, s, OCH3); 5.07 (1H, d, I = 4.5 Hz, 6-H); 5.38 (2H, br-s, NH 2); 5.95 (1H, d, I = 4.5 Hz, 7-H); 5.7-6.2 (1H, m, CH-CH-CH3); 6.81 (1H, s, thiazole-H);

  6.9-7.1 (2H, m; CH-CH3 and CH = CH-CH3); 7.55 (1H, d, I = 8 Hz, NH).

EXAMPLE 48

  Diphenylmethyl-7-r (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(triphenylphosphoranylidene) methyl] -3-cephem-4-carboxylate (VII, R2a = CH3)

  A solution of diphenylmethyl-7-E (Z) -2- (2-tritylamino) iodide

  thiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(triphenylphosphonio) methyl] -3

  Cephem-4-carboxylate (3.0 g, 2.5 mmol) in dichloromethane (40 mL) is shaken in the presence of 1N NaOH (10 mL) until the spot of the TLC starting material (gel) disappears. silica, CHCl3 / MeOH = 10/1). The organic layer is separated and concentrated under reduced pressure. The residue is triturated in the presence of n-hexane and the product collected by

  filtration to give 2.5 g (93%) of the title compound.

  IR: νmax (KBr) in cm 1: 1760, 1740, 1560.

  UV: X max (CH 2 Cl 2) in nm (c) 310 (8800), 388 (15000).

  * US 4,486,586, column 33, preparation No. 17, compound VIII-1.

EXAMPLE 49

  Diphénylm6thyl-7-r (Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyimino

  acetamidol-3-r3- (Z) -acetoxy-1-propenyl-3-cephem-4-carboxylate (VIII, R2a = CH3, R3 = OAc)

  A mixture of diphenylmethyl-7-F (Z) -2- (2-tritylaminothiazol-4-yl) -2-

  m6thoxyiminoacétamido] -3- (triphénylphosphoranylidane) methyl-3-cephem-4-

  carboxylate (2.13 g, 2.9 mmol) and acetoxyacetaldehyde (1) (0.61 g, 6.0 mmol) in dichloromethane (10 mL) was stirred for 3 hours at room temperature. The mixture is concentrated under reduced pressure and the residue is chromatographed on a column packed with silica gel. The column is eluted with n-hexane / CHCl 3 (1/2) and the fractions containing the desired product are pooled. Evaporation of the solvent

  under reduced pressure gives 1.0 g (56%) of the title compound.

  IR: νmax (νq) in cm1: 1785, 1735, 1675, 1430, 1230, 1180.

  NMR: δ (CCl4) in ppm: 6.08 (1H, d, I = 13 Hz).

  1) J. Corbet and C. Benezra, J. Org. Chem., 46, 1141 (1981).

EXAMPLE 50

  Diphenylmethyl-7-amino-3- (Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (XIII, R3 = OAc) To a cooled mixture of LiBr (8.6 g, 0.1 mole) in DMF

  (40 ml) is added successively a solution of diphenylmethyl-7-

  benzylideneamino-3-r (triphenylphosphoranylidene) methyl] -3-cephem-4-

  carboxylate (XI) (7.3 g, 10 mmol) in dry methylene chloride (200 mL) and acetoxyacetaldehyde (3.06 g, 0.03 mol), and the mixture is stirred at room temperature for 44 hours. After concentrating to 50 ml, the oily residue is dissolved in ethyl acetate and the solution is washed with water, saturated NaCl solution, dried over MgSO 4 and concentrated to 100 ml. To the stirred concentrate was added a solution of Girard T reagent (5 g, 0.03 mol) in methanol (100 ml) containing 1 ml of acetic acid and the mixture was stirred at room temperature for 40 minutes. After evaporation of the solvent, the residue is dissolved in 300 ml of ethyl acetate and the solution is washed with sodium bicarbonate solution, water, saturated NaCl solution and dried with MgSO4. Evaporation of the solvent gives an oily residue which is chromatographed on a column packed with silica gel (Merck Kieselgel 60, 100 g) and eluted with chloroform. The eluate is monitored by TLC (chloroform / methanol 30/1), the fractions which have a spot at Rf 0.30 are pooled and concentrated, giving an oily residue which is triturated in the presence of a mixture. ether / isopropyl ether for

  2.8 g (60%) of the title compound melting at 130-135 ° C (dec).

  IR: ν max (KBr) cm -1: 1770, 1720, 1390, 1370, 1220, 1100.

  UV: kmax (MeOH) in nm (F) 286 (7500).

  NMR: δ (CDCl 3) in ppm: 1.83 (2H, br s, NH 2); 2.02 (3H, s, COCH3); 3.27 (1H, d, I = 18 Hz, 2-H); 3.65 (1H, d, I = 18 Hz, 2-H); 3.9-4.9 (2H, m, CH 2 0Ac);

2583757

  4.78 (1H, d, I = 4.5 Hz, 6-H); 5.02 (1H, d, I = 4.5 Hz, 7-H); 5.3-5.8 (1H, m, = CH-CH 2); 6.27 (1H, d, I = 11 Hz, CH = CH-CH 2); 6.97 (1H, s, CH-Ph);

7.2-7.6 (1OH, m, phenyl-H).

  On analysis, we see that the product obtained has the formula:

C25H24N205S

  and the following values are obtained:

C H N S

  - calculated .......... 64.64 5.21 6.03 6.90 - found ........... 64.79 5, 33 5.89 6.94

EXAMPLE 51

  Diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (XIV, R3 = OAc)

  A mixture of diphenylmethyl-7-amino-3 - [(Z) -3-acetoxy-1-propenyl] -3-

  cephem-4-carboxylate (2.32 g, 5 mmol) and benzotriazol-1-yl (Z) -2- (2-

  aminothiazol-4-yl) -2-methoxyiminoacetate (1.9 g, 6 mmol) in 100 ml of dry THF is stirred at room temperature for 20 hours and the solvent is evaporated to dryness. After extraction with ethyl acetate (200 ml), the solution is washed with aqueous sodium bicarbonate, saturated NaCl solution and water, dried over MgSO 4 and concentrated to give an oily residue. It is then chromatographed on a column packed with silica gel (Merck Kieselgel 60, 80 g), eluting successively with chloroform and a chloroform / methanol mixture (50/1). The desired eluted fractions are combined with chloroform / methanol (50/1) and concentrated, to give a residue which is triturated in the presence of an ether / isopropyl ether mixture to obtain 1.97 g (61%). of the compound in

  heading melting at 120 C (Dec. prog.).

  IR: ν max (KBr) in cm 1: 1780, 1730, 1670, 1610, 1530, 1370, 1220, 1030.

  UV: λmax (MeOH) in nm (e) 286 (14000).

  NMR: δ (CDCl 3) in ppm: 1.97 (3H, s, COCH 3); 3.42 (2H, s, 2-H); 4.02 (3H, s, OCH3); 5.15 (1H, d, I = 4.5 Hz, 6-H); 6.03 (1H, d-d, I = 4.5 and 9 Hz, 7-H); 6.27 (1H, d, I = 11 Hz, CH = CH-CH 2); 6.78 (1H, s, thiazole-H); 6.94 (1H, s,

  CHPh); 7.2-7.6 (1OH, m, phenyl-H); 8.03 (1H, d, I = 9 Hz, NH).

EXAMPLE 52

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-E (Z) -3-acid

  acetoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia, R = CH3, R = OAc)

  A) From XIV (R3 = OAc) - A mixture of diphenylmethyl-7-E (Z) -

  2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 - [(Z) -3-acetoxy-1-

  propenyl] -3-cephem-4-carboxylate (1.88 g, 2.9 moles), 3 ml of anisole and 9 ml of TFA is stirred at room temperature for 10 minutes and the mixture is concentrated to 5 ml. . After dilution with 50 ml of ether and 1 ml of isopropyl ether, the resulting precipitate is collected by filtration to give 1.5 g of crude trifluoroacetate (R2 = CH3).

  R3 = OAc). Chromatography is carried out on a column packed with a garnish.

  sage from a PrepPAK C-18 cartridge (400 ml, Waters) and one elects

  successively with water and methanol at 20%. Fractions are collected

  The desired compositions were eluted with 20% methanol and concentrated to give a solid which was dissolved in 100 ml of methanol and treated with activated charcoal and concentrated to 10 ml. To the rapidly cooled concentrate is added ether (200 ml) and the resulting precipitate is collected by filtration, washed with ether and dried under vacuum over P2O5.

  to obtain 938 mg (67%) of the title compound, melting at 160 ° C (dec.

prog.).

  IR: V max (KBr) in cm 1770, 1720, 1670, 1620, 1530, 1370, 1230, 1030.

  UV: xmax (pH 7 phosphate buffer) in nm (E) 231 (17000), 284 (16000).

  NMR: δ (D20 + Na2CO3) in ppm: 2.22 (3H, s, COCH3); 3.47 (1H, d, I = 18 Hz, 2-H); 3.76 (1H, d, I = 18 Hz, 2-H); 4.13 (3H, s, OCH3); 5.39 (1H, d, I = 4.5 Hz, 6-H); 5.92 (1H, d, I = 4.5 Hz, 7-H); 6.36 (1H, d, I = 11 Hz,

  CH = CH-CH2); 7.14 (1H, s, thiazole-H).

  On analysis, we see that the product obtained has the formula:

C18H19N507S2. 1 / 2:20

  and the following values are obtained:

C H N S

  - calculated .......... 44.07 4.11 14.28 13.07 - found ............... 44.29 4.07 13.98 13.03

  B) From VIII (R2a = CH3, R3 = OAc) - Diphenyl-

  methyl-7- [E (Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3 - [(Z) -3-acetoxy-1-propenyl] methyl-3-cephem-4-carboxylate (1.0 g, 1.12 mmol);

  1c) in 85% formic acid (5ml) and the solution stirred for 2 hours at room temperature. Hydrochloric acid is added

  (0.1 ml) and stirring continued for a further 2 hours. After eliminating

  Excess formic acid is evaporated off, the mixture is triturated with isopropyl ether to precipitate the crude product which is collected by filtration and purified by chromatography to yield 154 mg.

  (31%) of the title compound, identical to that obtained by the

A.

EXAMPLE 53

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

* 3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R3 = OAc,

R = AX)

  To a cooled and stirred solution of (R2 = CH3, R3 = OAc) (362 mg, 0.75 mmol) in DMF (5 mL) was added K2Cl3 (312 mg, 2.25 mmol) and a solution of of 1-acetoxyethyl bromide (501 mg, 3 mmol) in DMF (1.5 ml) in three portions at 15 minutes intervals and the mixture is stirred for a further 30 minutes. After dilution with ethyl acetate (200 ml), the solution is washed with water, saturated NaCl solution, dried and evaporated to dryness. The oily residue is purified by chromatography on a column packed with silica gel (Merck Kieselgel 60, 40 g), eluting with

  successively with chloroform and chloroform / methanol (50/1).

  Fractions which peak at the retention time of 6.1 minutes were collected by HPLC and evaporated to dryness to give a residue which was triturated in the presence of ether to give 236 mg (68%) of the compound. in heading. Estimated purity: 60%. This compound contains about 25% of A2 isomer

  as impurity. Melting point: 110 C (Decr.

  IR: ν max (KBr) in cm -1: 1780, 1760, 1740, 1670, 1610, 1530, 1370, 1230,

1070, 1030.

  UV: Xmax (MeOH) in nm (c) 268 (15000).

  NMR: δ (CDCl13) in ppm: 1.51 (3H, d, I = 6 Hz, CH-CH3); 2.04 (3H, s, COCH3); 2.08 (3H, s, COCH3); 3.03 and 3.60 (1, SH, ABq, I = 18 Hz, 2-H); 4.05 (3H, s,

  OCH3); 6.17 (0.3H, s, A2-H); 6.26 (1H, d, I = 11 Hz, CH = CH-CH 2).

  * HPLC [Lichrosorb RP-18, 4 x 300 mm, 50% acetonitrile / buffer

pH 7)].

EXAMPLE 54

  Diphenylmethyl-7-amino-3-E (E) -3-acetoxy-1-propenyl] -3-cephem-4carboxylate (XIII (E), R = H, R4a = CHPh2)

  To a solution of diphenylmethyl-7-amino-3- [E (Z) -3-acetoxy-1

  propenyl] -3-cephem-4-carboxylate (2.7 g, 5.8 mmol) and acetophenone

  (720 mg, 6 mmol) in methanol (1 L), hydrochloric acid is added

  1N drique (6 ml). The solution was irradiated with a low pressure mercury lamp (2537 angstroms, 6 W) with stirring at room temperature for 22 hours and evaporated to dryness. The residue is dissolved in ethyl acetate (300 ml) and the solution is washed with aqueous sodium bicarbonate, water, saturated NaCl solution and dried over MgSO4. After evaporation of the solvent, the residue is chromatographed on a column packed with silica gel (Merck Kieselgel 60, 100 g) and eluted with chloroform. The fractions which reveal a spot at Rf 0.45 in TLF (chloroform / methanol = 30/1) are pooled and concentrated to obtain a residue. Trituration of the residue in the presence of ether gives

  210 mg (34%) of the title compound melting at 157 ° C (dec).

  This last fraction, having a spot A 0.40 in TLC, gives

  583 mg (22%) of the starting Z isomer.

  IR: ν max (KBr) in cm -1: 1760, 1730, 1710, 1360, 1240, 1210, 1090.

  UV: Xmax (MeOH) in nm (O) 301 (15000).

  NMR: δ (CDCl 3) δ ppm: 1.8 (2H, br s, NH 2); 2.02 (3H, s, COCH3); 3.56 (2H, s, 2-H); 4.73 (1H, d, I = 4.5 Hz, 6-H); 4.95 (1H, d, I = 4.5 Hz, 7-H); 6, 87

  (1H, d, I = 16 Hz, CH = CH-CH 2); 7.05 (1H, s, CHPh); 7.3-7.6 (1OH, m, Ph).

  On analysis, we see that the product obtained has the formula:

C25H24N205S

  and the following values are obtained:

C H N S

  - calculated .......... 64.64 5.21 6.03 6.72 - found ........... 64.28 5, 21 5.88 6.82

EXAMPLE 55

  Diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-méthoxyiminoacétamidol-

  3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (XIV (E), R 2 = CH 3, R 3 = OAc, R 4a = -CHPh 2)

  A mixture of diphenylmethyl-7-amino-3-E [(E) -3-acetoxy-1-propenyl] -3-

  cephem-4-carboxylate (930 mg, 2 mmol) and 1 - [(Z) -2- (2-aminothiazol)

  4-yl) -2-methoxyiminoacetoxy] benzotriazole (954 mg, 3 mmol) in dry THF (40 mL) is stirred at room temperature for 4 hours and the mixture is concentrated to dryness. The residue is dissolved in ethyl acetate (100 ml) and the solution is washed with aqueous sodium bicarbonate, water, saturated NaCl solution and dried over MgSO4. After evaporation of the solvent, the residue is chromatographed on a column packed with silica gel (Merck Kieselgel 60, 40 g), eluting with

  successively with chloroform and chloroform / methanol (50%).

  The desired fractions are collected and evaporated to dryness and the residue triturated with ether to give 910 mg (70%) of the title compound.

melting at 110 C (Dec. prog.).

  IR: ν max (KBr) in cm -1: 1780, 1730, 1680, 1610, 1530, 1380, 1220.

  UV: xmax (MeOH) in nm (c) 297 (22000).

642583757

  NMR: 6 (CDCl3) in ppm: 1.99 (3H, s, COCH3); 3.56 (2H, s, 2-H); 4.04 (3H, s, OCH3); 4.52 (2H, d, I = 6Hz, CH = CH-CH2); 5.08 (1H, d, I = 4.5 Hz, 6-H); 97 (1H, d-d, I = 8 and 4.5 Hz, 7-H); 5.7-6.2 (1H, m, CH = CH-CH2); 6.83 (1H,

s, thiazole-H); 6.96 (1H, s, CHPh).

EXAMPLE 56

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-methoxyiminoacetamido] - 3 - [(E) -3-) acid

  acetoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia (E), R = CH3, R3 = OAc)

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxy)

  iminoacetamido] -3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (870 mg,

  1.34 mmol) and anisole (0.8 ml) are dissolved in 2.4 ml of trifluorinated

  roacetic and the solution is stirred at room temperature for minutes. The reaction mixture is prepared and purified by a procedure similar to that described in Example 52 (procedure A),

  to give 429 mg (66%) of the title compound, mp 180 ° C (dec.

prog.).

  IR: νmax (KBr) in cm 1 1770, 1730, 1670, 1630, 1530, 1370, 1240, 1030.

  UV: Xmax (pH 7 phosphate buffer) in nm (e) 231 (17000), 292 (26000).

  NMR: 6 (D20 + Na2CO3) in ppm: 2.20 (3H, s, COCH3); 3.75 (2H, s, 2-H); 4, 10 (3H, s, OCH 3); 5.75 (2H, s, CH 2 0Ac); 5.32 (1H, d, I = 4.5 Hz, 6-H); 5.88 (1H, d, I = 4.5 Hz, 7-H); 5.9-6.3 (1H, m, CH = CH-CH 2); 6.73 (1H, d,

  I = 16 Hz, CH = CH-CH2); 7.09 (1H, s, thiazole-H).

EXAMPLE 57

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-méthoxylminoacétamido] -

  3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib (E), R 2 = CH 3, R = OAc, R = AX) to a stirred solution of Ia (E) (R2 = CH3, R3 = OAc) (241 mg, 0.5 mmol) in dry DMF (4 mL), K2CO3 (140 mg, 1 mmol) and a bromide solution of 1 Acetoxyethyl (336 mg, 2 mmol) in DMF (2 ml) in four portions at 15 minutes intervals, and the mixture is stirred at the same temperature for a further 1 hour. After dilution with ethyl acetate, the solution is washed with water and

  saturated NaCl solution, dried over MgSO4 and concentrated to dryness.

  The residue is chromatographed on a column packed with silica gel (Merck Kieselgel 60, 30 g) eluting sequentially with chloroform and with chloroform / methanol (50/1). The desired fractions are collected, eluted with chloroform / methanol, evaporated to dryness and triturated in the presence of ether to give 185 mg.

  (65%) of the title compound, melting at 120 ° C. (Dec. prog.).

  IR: ν max (KBr) in cm -1: 1770, 1680, 1620, 1500, 1390, 1240, 1080, 1040.

  UV: kmax (MeOH) in nm () 232 (18000), 295 (21000).

  NMR: δ (CDCl 3) δ ppm: 1.56 (3H, d, I = 6 Hz, CH-CH 3); 2.08 (6H, s, COCH3); 3.6 (2H, br-s, 2-H); 4.06 (3H, s, OCH3); 5.07 (1H, d, I = 4.5 Hz, 6-H); , 39 (2H, br-s, NH 2); 5.7-6.4 (2H, m, CH = CHCH2 and 7-H); 6.81 (1H, s,

  thiazole-H); 7.56 (1H, d, I = 8 Hz, NH).

EXAMPLE 58

  Diphenylmethyl-7- (Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyimino

  acetamido] -3-chloromethyl-3-cephem-4-carboxylate (IV, R2a = Tr)

  To a mixture of * (Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxy acid

  iminoacetic acid (6.71 g, 10 mmol) and 1-hydroxybenzotrial monohydrate

  (1.53 g, 11 mmol) in THF (50 ml), dicyclohexyl-

  carbodiimide (2.06 g, 10 mmol) at 5 ° C. and the mixture is stirred for 2 hours at the same temperature and filtered to give a solution

  active ester. A suspension of diphenylmethylhydrochloride is washed

  7-Amino-3-chloromethyl-3-cephem-4-carboxylate (4.51 g, 10 mmol) in ethyl acetate (50 ml) using saturated NaHCO3 solution (10 mg x 3), water and dry. The solution is poured into the solution of the active ester prepared above while stirring at 0 ° C. and the mixture is left to stand for 2 days at 5 ° C. After evaporation, the residue is chromatographed on a column packed with gel. silica (silica gel 60, g) and the column was eluted with CHCl3 / n-hexane (2/1). Fractions containing the desired product are concentrated under reduced pressure. Trituration of the residue in the presence of n-hexane gives 10.0 g

  (94%) of the title compound as an amorphous powder.

  IR: ν max (KBr) cm -1: 1780, 1720, 1680, 1490.

  UV: X max (CH2Cl2) in nm (-) 245 (23000).

  NMR: α (CDCl13) in ppm: 3.4 (2H, ABq, I = 12 Hz, 2-H); 5.02 (1H, d, I = 4 Hz, 6-H); 6.01 (1H, d-d, I = 4 and 6Hz, 7-H); 6.45 (1H, s,

  thiazole-H); 7.00 (1H, s, CHPh 2); 7.1-7.7 (40H, phenyl-H).

  * R. Bucourt et al., Tetrahedron, 34, 2233 (1978).

EXAMPLE 59

  Diphenylmethyl-7 {(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyimino-

  acetamido] -3- (triphenylphosphoranylidene) methyl-3-cephem-4-carboxylate (VII, R2a = Tr)

  A mixture of diphenylmethyl-7- (Z) -2- (2-tritylaminothiazol-4-yl) -2-

  trityloxyiminoacetamido-3-chloromethyl-3-cephem-4-carboxylate (9.9 g,

66 2583757

  9.3 mmol) and NaI (11 g, 73 mmol) in acetone (100 mL) is stirred for 30 minutes at room temperature and concentrated under reduced pressure. The residue is diluted with ethyl acetate (100 ml) and the mixture is washed with 10% aqueous Na2S2O3 solution (50 ml x2) and water. Triphenylphosphine (3.93 g, 15 mmol) is added to the mixture.

  1a) and the mixture is stirred for 3 hours at room temperature.

  After evaporation, the residue is triturated in the presence of isopropyl ether and

  collects the precipitate by filtration, which gives the salt of phosphorus

  nium (14.2 g). It is dissolved in CH 2 Cl 2 (100 ml) and the solution is washed.

  with 1N NaOH (about 50 ml) until the phosphonium salt is complete

  It was converted to the ylide while monitoring by TLC (Merck 60 F254 silica gel, CHCl3 / MeOH 10: 1). The organic layer is separated, washed with water and concentrated under reduced pressure. Triturate the residue in the presence of isopropyl ether to give 12.0 g (94%) of the title compound.

heading.

  IR: ν max (KBr) in cm -1: 1760, 1740, 1650, 1480.

  UV: X max (CH 2 Cl 2) in nm (E) 310 (9200), 388 (16200).

EXAMPLE 60

  Diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -2-trityloxyimino-

  acetamido] -3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (VIII, R2a = Tr, R = OAc)

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -

  2-trityloxyiminoacétamido] -3- (triphenylphosphoranylidene) methyl-3-cephem

  4-carboxylate (2.58 g, 2 mmol) and acetoxyacetaldehyde (612 mg, 3 mmol) were

  the) in dichloromethane (10 ml) is stirred overnight at room temperature and concentrated under reduced pressure. The residue is chromatographed on a column packed with silica gel (Merck silica gel 60, 50 g) and the column is eluted with a mixture

  toluene / ethyl acetate (9/1). Evaporation of the fractions which contain

  The desired product gives 1.0 g (45%) of the title compound.

  IR: ν max (KBr) in cm -1: 1780, 1730, 1680, 1520, 1220.

  UV: X max (CH 2 Cl 2) in nm (c) 305 (12200).

  NMR: a (CDCl3) in ppm: 2.00 (3H, s, COCH3); 3.20 (2H, ABq, I = 18 Hz, 2-H); , 1 (1H, d, I = 4 Hz, 6-H); 6.20 (1H, d, I = 11Hz, = CH); 6.48 (1H, s,

  thiazole-H); 6.95 (1H, s, CHPh 2); 7.1-7.6 (40H, phenyl-H).

  J. Corbet and C. Benezra, J. Org. Chem., 46, 1141 (1981).

EXAMPLE 61

  7-E (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] - 3 - [(Z) -3-) acid

  acetoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = H, R3 = OAc)

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -

  2-trityloxyiminoacetamido] -3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (3.29 g, 2.94 mmol) and 85% formic acid (15 ml) is stirred for 2 hours at room temperature. Concentrated hydrochloric acid (0.6 ml) was added to the solution and the mixture was stirred for 2 hours. After evaporation of the solvent, the residue is triturated in the presence of isopropyl ether to give 1.2 g of a crude product which is chromatographed on a column packed with silica gel C-18 (20 mm × 200).

  mm) eluting with 20% MeOH. Fractions which contain

  The desired product is obtained and concentrated to a small volume under reduced pressure. Lyophilization of the concentrate gives 412 mg (30%) of the compound

  heading, melting at 180 C (dec.). Estimated purity: 60%.

  IR: ν max (KBr) in cm 1760, 1620, 1530, 1370, 1240.

  UV: Xmax (pH 7 phosphate buffer) in nm (υ) 279 (15300).

  NMR: δ (DMSO-d6) in ppm: 2.00 (3H, s, COCH3); 4.50 (2H, d, I = 8 Hz, CH 2 O); 15 (1H, d, I = 4 Hz, 6-H); 6.30 (1H, d, I = 12 Hz, = CH-); 6.65 (1H, s, thiazol-H); 7.00 (2H, s, NH 2); 9.40 (1H, d, I = 8 Hz, 7-CONH); 11.30 (1H,

s, = N-OH).

EXAMPLE 62

  1-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -

  3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R = H, R = OAc,

R = AX)

2 3

  To a stirred solution of Ia (R = H. R3 = OAc) (280 mg, 0.6 mmol) in dry DMF (2 mL) was added at -5 C Na2CO3 (105 mg, 1 mmol) and a 1-acetoxyethyl bromide solution (396 mg, 2.37 mmol) in DMF (2 mL) in three portions at 20 minutes intervals, and the mixture was stirred for a further 10 minutes. After dilution with ethyl acetate, the solution is washed with water and concentrated under reduced pressure. Trituration of the residue with isopropyl ether gives 195 mg of crude product which is chromatographed on a column packed with silica gel (25 g). The column is eluted with chloroform containing 1 to 2% methanol, the fractions containing the desired product are combined and concentrated under reduced pressure. Trituration of the product in the presence of isopropyl ether gives 75 mg (23%) of the product melting at 100 ° C.

(Dec.). Estimated purity: 70%.

  IR: V max (KBr) in cm 1 1780-1730, 1670, 1530, 1380, 1240.

  UV: Xmax (CH2Cl2) in nm (e) 249 (17300).

  NMR: δ (CDCl 3) in ppm: 1.0 (3H, d, I = 5 Hz, CH-CH 3); 2.03 (3H, s, COCH3); 2.05 (3H, s, COCH3); 5.10 (1H, d, I = 4 Hz, 6-H); 6.30 (1H, d, I = 12 Hz, = CH-); 6.95 (1H, s, thiazole-H).

COMPOUND 33, EXAMPLE 63

  7 - [(Z) -2- (2-aminothiazol-4-yl) -2-hydoxyiminoacetamido] -3 - [(E) -) acid

  1-propenyl] -3-cephem-4-carboxylic acid (Ia (E), R 2 = H, R = H) A mixture of crude VIII (R a = Tr, R 3 = H) containing 20% of its E isomer (9 2 g, 8.7 mmol) in 85% HCOOH (60 ml) is stirred for 1 hour at room temperature and evaporated in vacuo. The residue is treated with 90% TFA (60 ml) for 1 hour at room temperature and poured into ice water (300 ml). The insolubles are removed by filtration. The filtrate is chromatographed on a reverse phase column (Waters, PrepPAK C18, 300 ml) and the column is eluted with% MeOH. The polar fractions are pooled, concentrated in vacuo and triturated in the presence of isopropyl ether to give 1.15 g (33%) of the Z isomer (Ia, R2 = R3 = H) and the fractions less polar give

  143 mg (4%) of the title compound. Melting point:> 200 C (dec.).

  IR: νmax (KBr) in cm 1: 1760, 1660, 1630, 1530.

  UV: Xmax (phosphate buffer pH 7) in nm (e) 223 (20000), 290 (21000).

  1H NMR (D20) d: 1.38 (3H, d, I = 7.0 Hz); 3.73 (2H, br.s); 5.30 (1H, br.s); , 83 (1H, d, I = 5.0 Hz); 5.80-6.30 (1H, m); 6.57 (1H, d, I = 16 Hz);

7.06 (1H, s).

  On analysis, we see that the product obtained has the formula:

C15H15N505S2. 1 S5H20

  and the following values are obtained:

C H N S

  - calculated ....... 41,28 4,16 16,05 14,65 - - found ........... 41,46. 3.6Q 15.86 14.83

COMPOUND 40, EXAMPLE 64

  Pivaloyloxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -

  3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R 2 = H, R 3 = OAc,

R4 = PV)

  To an ice-cold mixture of Ia (R2 = H, R3 = OAc) (170 mg, 0.36 mmol) and Na2CO3 (20 mg, 0.19 mmol) in dry DMF (2 mL) was added pivaloyloxymethyl iodide (87 mg, 0.36 mmol) and shaken

69 2583757

  mixing for 10 minutes at the same temperature. Additional pivaloyloxymethyl iodide (87 mg) and Na2CO3 (20 mg) were added and the mixture was stirred for a further 10 minutes. We dilute the mixture with

  ethyl acetate, washed with water and evaporated under reduced pressure.

  Chromatography of the residue on a column packed with silica gel and elution with CHCl3 / MeOH (1-2%) gives the product as an amorphous powder. Yield 110 mg (52%). Fusion point:

-100 C (dec.).

  IR: V max (KBr) in cm -1: 1780, 1740, 1670, 1530.

  UV: max (EtOH) in nm (E) 280 (11400).

  1kmax H NMR (CDCl3) δ: 1.20 (9H, s, t-Bu); 2.0 (3H, s, OAc); 3.45 (2H, s, 2-H); 4.50 (2H, d, I = 7 Hz, CH 2 0Ac); 5.10 (1H, d, I = 5 Hz, 6-H); 5.3-6.0 (4H, m, 7-H, vinyl-H, CH 2 CO); 6.25 (1H, d, I = 12 Hz, vinyl-H); 7.0 (1H, s,

  thiazole-H); 11.5 (1H, d, I = 8 Hz, CONH).

COMPOUND 41, EXAMPLE 65

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3 - [(E) -3-) acid

  acetoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia (E), R 2 = H, R 3 = AOc) a) Acylation to a solution of 1-hydroxybenzotriazole (223 mg, 1.44 mmol) and (Z) -2- (2-Tritylaminothiazol-4-yl) -2-trityloxyiminoacetic acid (1.06 g, 1.44 mmol) in THF (14 ml) was added DCC (300 mg, 1.44 g); mmoles) and

  the mixture is stirred for 1 hour at 5 ° C. Diphenylmethyl-7 is added.

  amino-3-E (E) -acetoxy-1-propenyl] -3-cephem-4-carboxylate (670 mg, 1.44 mmoles).

  the) to the mixture. After stirring for 4 hours at room temperature, the reaction mixture is filtered, diluted with ethyl acetate (50 ml) and washed with water. The concentration of the organic layer gives an oil which is chromatographed on a column packed with silica gel. Elution with toluene / ethyl acetate (10/1)

  gives 1.607 g (99%) of diphenylmethyl-7-E (Z) -2- (2-tritylaminothiazol-4-

  yl) -2-trityloxyiminoacétamido] -3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-

  carboxylate in the form of an amorphous powder.

  IR: νmax (KBr) in cm-1: 1770, 1730.

  1H NMR (CDCl3)?: 2.0 (3H, s, OAc); 3.33 (2H, s, 2-H); 4.54 (2H, ABq, CH 2 0Ac); 5.04 (1H, d, I = 5 Hz, 6-H); 6.0 (1H, m, vinyl-H); 6.02 (1H, dd, I = 5 and 7 Hz, 7-H); 6.40 (1H, s, thiazole-H); 6.82 (1H, d, I = 15 Hz,

  vinyl-H); 7.00 (1H, s, Ph 2 CH); 7.3 (25H, s, Ph).

2583757

b) Unlock

  A mixture of diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -

  2-trityloxyiminoacétamido] -3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-

  carboxylate (1.98 g, 1.75 mmol) in formic acid (20 ml) is stirred for 2 hours at room temperature. Concentrated hydrochloric acid (0.16 ml, 1.92 mmol) was added to the mixture and the mixture was stirred for 1 hour at room temperature. Filtration and concentration of the filtrate followed by trituration in the presence of IPE gives 975 mg of the crude product. Chromatography on a reverse phase column packed with silica gel and elution with 10% MeOH in water and a concentration of the fraction which contains the desired product gives 418 mg (51%) of the compound in heading in the form of a

amorphous powder.

  IR: V max (KBr) in cm 1: 1765, 1730, 1650.

  UV: Xmax (pH 7 phosphate buffer) in nm (E) 290 (23400).

  1H NMR (DMSO-d6) δ: 2.03 (3H, s, OAc); 3.65 (2H, Abq, 2-H); 4.61 (2H, Abq, CH 2 0Ac); 5.15 (1H, d, I = 5 Hz, 6-H); 5.75 (1H, dd, I = 5 and 8 hz, 7-H); 6.15 (1H, m, vinyl-H); 6.65 (1H, s, thiazole); 6.85 (1H, d, I = 15 Hz,

vinyl-H); 7.05 (2H, s, NH 2).

COMPOUND 44, EXAMPLE 66

  Pivaloyloxymethyl 7-E (Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino

  acetamido] -3 - [(E) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib (E), R 2 = H, R 3 = OAc, R 4 = PV) to a cooled and stirred mixture of Ia (E) (R2 = H, R3 = OAc) (200 mg, 0.43 mmol) and Na2CO3 (22.7 mg, 0.22 mmol) in DMF (2 mL) was added. pivaloyloxymethyl iodide (91 mg, 0.43 mmol) and the mixture is stirred at 5 ° C. for 30 minutes. The reaction mixture is diluted with ethyl acetate (40 ml), washed successively with water and with brine. The organic layer is dried over MgSO 4 and concentrated under reduced pressure. The crude product is chromatographed on a column packed with silica gel. Elution with CHCl3 / MeOH (1

  at 3%) gives 125 mg (50%) of the product as an amorphous powder.

  IR: ν max (KBr) in cm -1: 3300, 2970, 1780, 1740.

  UV: X max (MeOH) in nm (c) 296 (18500).

  1H NMR (DMSO-d6) a: 1.22 (9H, s, t-Bu); 2.08 (2H, s, OAc); 3.60 (2H, s, 2H); 4.66 (2H, ABq, CH 2 0Ac); 5.06 (1H, d, I = 5 Hz, 6-H); 5.85 (1H, dd, I = 5 and 7 Hz, 7-H); 5.88 (2H, ABq, 4-CO 2 CH 2); 6.0 (1H, m, vinyl-H); 7.00

  (1H, s, thiazole); 7.1 (1H, d, I = 15 Hz, vinyl-H).

71 2583757

COMPOUND 46, EXAMPLE 67

  Acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -

  3-E (Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R2 = CH3, R = OAc, R = AM) to a stirred and cooled solution of 240 mg (0, 5 mmol) of Ia (R 2 = CH 3, R 3 = OAc) in 4 ml of dry DMF, K 2 CO 3 (138 mg, 1 mmol) and acetoxymethyl bromide solution (306 mg, 2 mmol) are added at 0 ° C. in DMF (2 ml) in four portions at 15 minute intervals, and the mixture is stirred at 0 ° C for a further 10 minutes. After dilution with 100 ml of ethyl acetate, the mixture is washed with water and saturated NaCl solution and dried over MgSO4. After removing the solvent, the oily residue is purified by column chromatography.

  silica gel (Merck Kieselgel 60, 30 g). The successor column is elected

  with chloroform and with chloroform / methanol (50/1 -

  20/1). The fractions eluted with the chloroform / methanol (50/1) mixture are collected and evaporated. The residue is triturated in the presence of an ether / n-hexane mixture to give 72 mg (26%) of the desired product.

  melting at 90-95 ° C (dec). Estimated purity: 80%.

  IR: ν max (KBr) in cm 1: 1770, 1730, 1670, 1610, 1530, 1370, 1230, 1030.

  UV: X max (MeOH) in nm (s) 230 (17000), 287 (13000).

  1H NMR (CDCl3) 6: 2.02 (3H, s, OAc); 2.12 (3H, s, OCOCH3); 3.33 (1H, d, I = 18 Hz, 2-H); 3.60 (1H, d, I = 18 Hz, 2-H); 4.04 (3H, s, OCH3); 4.4-4.6 (2H, m, CH 2 COCH 3); 5.12 (1H, d, I = 4.5 Hz, 6-H); 5.38 (2H, br-s, NH 2); 82 (2H, s, COOCH20Ac); 5.4-5.9 (1H, m, CH = CHCH2); 5.98 (1H, dd, I = 8 and 4.5 Hz, 7-H); 6.29 (1H, d, I = 11 h, CH = CH-CH 2); 6.82 (1H, s, thiazole-H);

7.55 (1H, d, I = 8 Hz, NH).

COMPOUND 63, EXAMPLE 68

  7 - [(Z) -2- (2-Aminothiazol-4-yl) -2-acetoxyiminoacetamido] -3 - [(Z) -3- acid

  acetoxy-1-propenyl] -3-cephem-4-carboxylic acid (Ia, R2 = Ac, R3 = OAc)

a) Acylation

  To a mixture of (Z) -2- (tritylaminothiazol-4-yl) -2-acetoxyimino acid

  Acetic acid (1.95 g, 4.0 mmol) and 1-hydroxybenzotriazole (600 mg, 4.0 mmol) in THF (14 mL) were added DCC (824 mg, 4.0 mmol) and shaken. mixing for 1 hour in an ice bath. Diphenylmethyl-7-amino-3-E (Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (1.30 g, 2.8 mmol) is added to the suspension and the mixture is stirred for 4 hours at room temperature, filter and dilute with

72 2583757

  AcOEt (60 ml). The organic phase is washed with water, dried over MgSO 4 and concentrated under reduced pressure. The residue is passed through a column packed with silica gel (Wakogel C200, 80 g) and eluted with toluene / AcOEt (6/1). The fractions containing the product are pooled and concentrated in vacuo to give 2.01 g (77%) of diphenylmethyl.

  7 - [(Z) -2- (tritylaminothiazol-4-yl) -2-acétoxyiminoacétamido] -3 - [(Z) -3-

  acetoxy-1-propenyl-3-cephem-4-carboxylate (VIII, R 2a = Ac, R 3 = OAc).

IR: V max (KBr) cm -1: 1780, 1730.

  1H NMR (CDCl3) δ: 2.0 (3H, s, CH3CO); 2.15 (2H, s, CH3CO); 3.45 (2H, ABq, 2-H); 4.20 (2H, ABq, CH 2 0Ac); 5.12 (1H, d, I = 5 Hz, 6-H); 5.70 (1H, m; 3CH = CH); 5.90 (1H, dd, I = 5 and 7 Hz, 7-H); 6.26 (1H, d, I = 12 Hz,

  3-CH = CH); 6.95 (1H, s, thiazole); 7.30 (25H, s, phenyl).

b) Unlock

  A mixture diphenylmethyl-7 - [(Z) -2- (2-tritylaminothiazol-4-yl) -2-

  acetoxyiminoacetamido] - 3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (3.2 g, 3.43 mmol) in TFA (20 mL) and anisole (5 mL) It is stirred for 1 hour at 5 ° C. Removal of the solvent which is followed by trituration in the presence of 100 ml of isopropyl ether gives 1.25 g of TFA salt. The crude product is purified by chromatography using a column packed with Bondapak C-18, and eluted successively with water,

  10% MeOH in H2O and 20% MeOH in H2O. We bring together the fragments

  appropriate, concentrated in vacuo and lyophilized to give

  395 mg (23%) of the title compound.

  IR: ν max (KBr) in cm -1: 3300, 1770, 1670.

  UV: Xmax (pH 7 phosphate buffer) in nm (c) 228 (20300), 284 (15300).

  1H NMR (DMSO-d6) a: 2.0 (3H, s, CH3CO); 2.15 (3H, s, CH3CO); 4.51 (2H, ABq, CH2-OAc); 5.22 (1H, d, I = 5 Hz, 6-H); 5.60 (1H, m, 3-CH = CH); 5.80 (1H, dd, I = 5 and 7 Hz, 7-H); 6.32 (1H, d, I = 12 Hz, 3-CH = CH); 7.05 (1H, s, thiazole).

COMPOUND 65, EXAMPLE 69

  1-acetyloxy-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-acetoxyiminoacêtamido] -

  3 - [(Z) -3-acetoxy-1-propenyl] -3-cephem-4-carboxylate (Ib, R 2 = Ac, R 3 = OAc,

R = AX)

  To a solution of Ia (R 2 = Ac, R 3 = OAc) (248 mg, 0.49 mmol) in 25 ml of dry DMF was added Na 2 CO 3 (51 mg, 0.49 mmol) and acetoxyethyl bromide (82). mg, 0.49 mmol) at -10 ° C. The mixture is stirred at 5 ° C.

  30 minutes and 82 mg (0.49 mmol) of acetoxy bromide are added.

73 2583757

  ethyl to the suspension. After stirring for a further 30 minutes, the reaction mixture was diluted with AcOEt (50 mL), washed with water (30 mL x 3)

  and brine, dried over MgSO 4 and evaporated under reduced pressure.

  The crude product is purified by chromatography on silica gel eluting with 3% MeOH in chloroform. Removal of the solvent in the appropriate eluent followed by lyophilization gives 157 mg (54%) of

  present compound, melting point 125 C (dec).

  IR: ν max (KBr) in cm -1: 3430, 3290, 1770, 1680.

  UV: λ max (pH 7 phosphate buffer) in nm (E) 228 (21900), 287 (12700).

  1H NMR (DMSO-d6) δ: 1.51 (3H, d, I = 6Hz, 4-COOCHCH3); 2.02 (3H, s, AcO); 2.06 (3H, s, AcO); 2.22 (3H, s, AcO); 3.47 (3H, br.s, 2-H); 4.46 (1H, d, I = 6Hz, 4-COOCHCH3); 4.55 (2H, ABq, CH 2 0Ac); 5.12 (1H, d, I = 5 Hz, 6-H); 70 (1H, m, E-CH = CH-); 5.95 (1H, dd, I = 5 and 7 Hz, 7-H); 6.25 (1H, d,

  I = 12 Hz, 3-CH = CH); 6.92 (1H, s, thiazole).

COMPOUND 88, EXAMPLE 70

  (5-methyl-2-oxo-1,3-dioxolen-4-yl) -methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -

  2-hydroxyiminoacetamido] -3 - [(Z) -1-propenyl] -3-cephem-4-carboxylate (Ib,

R = H, R = H, R = -CH2 - | CH3

* 0

  To an ice-cooled and stirred solution of Ib (R 2 = H, R 3 = H) (512 mg, 1.25 mmol) in DMF (2 mL) was added sodium carbonate.

  (238.5 mg, 4.5 mmol) and a solution of 4-bromomethyl-5-methyl-1,3-

  dioxolene-2-one (869 mg, 4.5 mmol) in DMF (6 ml) in three portions at

  intervals of 15 minutes. The mixture is diluted with ethyl acetate

  (50 ml), washed with water and brine and dried over MgSO4.

  The filtrate is concentrated under vacuum. The residue is dissolved in a small amount of chloroform and purified by chromatography on a column packed with silica gel (Kieselgel 60, 30 g). The desired fractions are collected, eluted with a mixture of chloroform and methanol (30/1) and concentrated in vacuo to give 182 mg (29%) of

  sought product. Melting point: 115-120 ° C (dec).

  IR: V max (KBr) in cm -1: 1820, 1770, 1735, 1530, 1210, 1190.

  UV: λmax (EtOH) in nm (c) 225 (shl9000), 287 (12000).

  1 H NMR (CDCl3 + D20) δ: 1.62 (3H, d, I = 6.0 Hz); 2.18 (3H, s); 3.45 (2H, br, s); 4.68 (2H, s); 5.10 (1H, d, I = 5.5 Hz); 5.50-5.90 (1H, m); 5.85

  (1H, d, I = 5.5 Hz); 6.12 (1H, d, I = 12 Hz); 6.95 (1H, s).

742583757

COMPOUND 89, EXAMPLE 71

  1-éthoxycarbonyloxyéthyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2-hydroxyimino

  acetamido] -3-E (Z) -1-propenyl] -3-cephem-4-carboxylate (Ib, R = H, R3 = H, R4 = CH3CHOC00Et) To a stirred solution of Ib (R2 = H, R3 = 256 mg, 0.625 mmol) in DMF (2 mL) was added sodium carbonate (40 mg, 0.625 mmol) and a solution of α-iododiethylcarbonate (183 mg, 0.625 mmol) in DMF. (1 ml) at 0-5 C. After stirring the mixture for 20 minutes at 5 ° C.,

  sodium carbonate (40 mg) and a solution of iododiethyl-

  carbonate (183 mg) and the mixture is stirred for 40 minutes. The mixture is diluted with ethyl acetate (50 ml), washed with water (50 ml x 2), dried over MgSO 4 and filtered. The filtrate is concentrated under vacuum. The residue is dissolved in a small amount of chloroform and purified by chromatography on a column packed with silica gel (Kieselgel 60, 20 g). The desired fractions are eluted with a mixture of chloroform and methanol (30/1), combined and concentrated in vacuo,

  gives 56 mg (17%) of the desired product. Melting point: 105-110 C.

  IR: V max (KBr) in cm -1: 1760, 1525, 1370, 1270.

  UV: Xmax (EtOH) in nm (e) 222 (20000), 286 (11000).

  1H NMR (CDCl3 + D20) δ: 1.33 (3H, t, I = 7Hz); 1.57 (3H, d, I = 5 Hz); 1.70 (3H, d, I = 7 Hz); 3.45 (2H, br.s); 4.23 (2H, q, I = 7Hz); 5.10 (1H, d, I = 5.0 Hz); 5.87 (1H, d, I = 5.0 Hz); 5.50-6.00 (1H, m); 6.16 (1H, d,

  I = 12 Hz); 6.92 (1H, q, I = 5Hz); 7.00 (1H, s).

2583757

Claims (113)

1.- A compound of formula: s | 3CONr3- R EN 5 TAJ Gil N N> LCHi = CHiCH R R NGR2! ___ 2 COOR in which:   R1 represents a hydrogen atom or a classically protective amino group;   if that; R2 represents a hydrogen atom, a straight or branched alkyl chain   containing from 1 to 4 carbon atoms, an alkenyl or alkyl radical   nyl having 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, cycloalkylalkyl having 3 to 6 ring members and 4 to 10 carbon atoms or alkanoyl having 2 to 4 carbon atoms;   R3 represents a hydrogen atom, a lower alkyl radical   1 to 3 carbon atoms, lower alkoxy containing 1 to 3 carbon atoms, lower alkanoyloxy containing 2 to 3 carbon atoms; and R4 represents a hydrogen atom or a physiologically hydrolysable ester group. 2. The compound according to claim 1, wherein R1 represents a hydrogen atom, R2 represents a hydrogen atom, a methyl radical,   ethyl, isopropyl, cyclopropylmethyl, allyl, propargyl or acetyl.   3. The compound of claim 2, wherein R2 represents a hydrogen atom.   4. The compound according to claim 3, wherein R3 represents a hydrogen atom.   5. The compound of claim 4, wherein R4 represents a hydrogen atom.   6. The compound of claim 5 which is 7B - [(Z) -2-   (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -prop-l-en-1-yl] - 3-cephem-4-carboxylic acid.   7. The compound of claim 5, which is 78 - [(Z) -2-   (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -. Prop-1-en-1-yll-   3-cephem-4-carboxylic acid. 8. The compound of claim 4 wherein R4 is acetoxymethyl.   9. The compound of claim 8 which is acetoxymethyl   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -prop   1-ene-1-yl] -3-cephem-4-carboxylate.   10. The compound of claim 8 which is acetoxymethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -prop   1-en-l-yl] -3-cephem-4-carboxylate. 11. The compound according to claim 4, wherein R4 represents the 1-acetoxyethyl.   12. The compound of claim 11 which is 1-acetoxyethyl-   78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -prop   1-en-l-yl] -3-cephem-4-carboxylate.   13. The compound of claim 11, which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -prop   1-en-l-yl] -3-cephem-4-carboxylate. 14. The compound of claim 4 wherein R4 is pivaloyloxymethyl.   15. The compound according to claim 14, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -   prop-l-ene-l-yl] -3-cephem-4-carboxylate.   16. The compound according to claim 14, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -   prop-l-ene-l-yl] -3-cephem-4-carboxylate. 17. The compound of claim 3 wherein R3 is acetoxy. 18. The compound of claim 17, wherein R4 is a hydrogen atom.   19. The compound of claim 18 which is 78 - [(Z) -   2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -3-acétoxyprop-   1-en-l-yl] -3-cephem-4-carboxylic acid.   20. The compound of claim 18, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -3-acétoxyprop-   1- & does-l-yl] -3-cephem-4-carboxylic acid. 21. The compound of claim 17 wherein R4 is acetoxymethyl.   22. The compound of claim 21 which is acetoxymethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -3-   acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   23. The compound according to claim 21 which is acetoxymethyl   77 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -3acétoxyprop-1-en-1-yl] -3-cephem 4-carboxylate. The compound of claim 17, wherein R4 is 1-acetoxyethyl.   The compound of claim 24, which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -3-   acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 24, which is 1-acetoxyethyl-   76 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -3-   acétoxyprop-l-en-1-yl] -3-cephem-4-carboxylate. The compound of claim 17, wherein R4 is pivaloyloxymethyl.   28. The compound according to claim 27, which is pivaloyloxy   methyl-7-E (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -   3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   29. The compound according to claim 27 which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(E) -   3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate. The compound of Claim 2 wherein R2 is methyl. The compound of claim 30, wherein R represents a hydrogen atom.   32. The compound of claim 31, wherein R4 is a hydrogen atom.   33. The compound according to claim 32, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -prop-1-ene 1-yl] -3-cephem-4-carboxylic acid.   34. The compound according to claim 32, which is 7e - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -prop-1-ene   1-yl] -3-cephem-4-carboxylic acid. The compound of claim 31, wherein R4 is 1-acetoxyethyl.   36. The compound according to claim 35, which is 1-acetoxyethyl-   78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -prop-1- en-1-yl] -3-cephem-4-carboxylate.   37. The compound of claim 35 which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -prop-1ene-1-yl] -3-cephem-4-carboxylate . 38. The compound according to claim 31, wherein R4 represents pivaloyloxymethyl.   39. The compound according to claim 38, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   prop-l-ene-1-yl] -3-cephem-4-carboxylate.   40. The compound according to claim 38, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   prop-1-en-1-yl] -3-cephem-4-carboxylate. 41. The compound according to claim 30, wherein R3 represents methyl.   42. The compound according to claim 41, wherein R4 represents a hydrogen atom.   43. The compound according to claim 42, which is 7e - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -but-l-en-1-yl] - 3-cephem-4-carboxylic acid.   44. The compound of claim 42 which is 78 - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -but-1-ene-1-yl] -   3-cephem-4-carboxylic acid. The compound of claim 41, wherein R4 is acetoxymethyl.   46. The compound according to claim 45, which is acetoxymethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -but-1- en-1-yl] -3-cephem-4-carboxylate.   47. The compound according to claim 45, which is acetoxymethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -but-1-   ene-1-yl] -3-cephem-4-carboxylate. 48. The compound according to claim 41, wherein R4 represents 1-acetoxyethyl.   49. The compound according to claim 48, which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -but-1- ene-l-yl] -3-cephem-4-carboxylate.   50. The compound according to claim 48 which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -but-1-   ene-l-yl] -3-cephem-4-carboxylate. 51. The compound of claim 41, wherein R4 is pivaloyloxymethyl.   52. The compound according to claim 51, which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   but-l-ene-l-yl] -3-cephem-4-carboxylate.   53. The compound according to claim 51, which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   but-l-ene-l-yl] -3-cephem-4-carboxylate. 54. The compound according to claim 41, wherein R4 represents 4-glycyloxybenzoyloxymethyl.   55. The compound of claim 54 which is 4-glycyloxy-   benzoyloxymethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -   acetamido] -3 - [(Z) -but-l-ene-l-yl] -3-cephem-4-carboxylate.   56. The compound of claim 54, which is 4-glycyloxy-   benzoyloxymethyl-76 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) -   acetamido] -3 - [(E) -but-l-ene-l-yl] -3-cephem-4-carboxylate. 57. The compound of claim 30, wherein R3 is ethyl. 58. The compound according to claim 57, wherein R4 represents a hydrogen atom.   59. The compound according to claim 58, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -pent-1-ene 1-yl] -3-cephem-4-carboxylic acid.   60. The compound of claim 58 which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -pent-l-ene   1-yl] -3-cephem-4-carboxylic acid. 61. The compound according to claim 57, wherein R4 represents 1-acetoxyethyl.   62. The compound of claim 61, which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-E (Z) -pent-   1-en-l-yl] -3-cephem-4-carboxylate.   63. The compound of claim 61, which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -pent-   1-en-l-yl] -3-cephem-4-carboxylate. 64. The compound according to claim 57, wherein R4 represents pivaloyloxymethyl.   65. The compound according to claim 64, which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   pent-1-en-1-yl] -3-cephem-4-carboxylate.   66. The compound according to claim 64, which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   pent-1-ene-1-yl] -3-cephem-4-carboxylate. The compound of claim 30, wherein R 3 represents methoxy.   68. The compound according to claim 67, wherein R4 represents a hydrogen atom.   69. The compound according to claim 68, which is acid 78 - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -3-méthoxyprop-   1-ene-1-yl] -3-cephem-4-carboxylic acid.   70. The compound according to claim 68, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -3-méthoxyprop-   1-ene-1-yl] -3-cephem-4-carboxylic acid. 71. The compound according to claim 67, wherein R4 represents 1-acetoxyethyl.   72. The compound of claim 71, which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -3-   methoxyprop-l-en-1-yl] -3-cephem-4-carboxylate.   73. The compound according to claim 71, which is 1-acetoxyethyl-   78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3-E (E) -3-   methoxyprop-l-ene-l-yl] -3-cephem-4-carboxylate. The compound of claim 67, wherein R4 is pivaloyloxymethyl.   75. The compound according to claim 74, which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   76. The compound according to claim 74, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   3-methoxyprop-1-en-1-yl] -3-cephem-4-carboxylate. 77. The compound according to claim 30, wherein R3 represents an acetoxy.   78. The compound of claim 77, wherein R4 is a hydrogen atom.   79. The compound according to claim 78, which is 7e - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -3-acétoxyprop-   1-ene-1-yl] -3-cephem-4-carboxylic acid.   80. The compound of claim 78 which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -3-acétoxyprop1-en-1-yl] -3-cephem-4-carboxylic acid. 81. The compound of claim 77, wherein R4 is acetoxymethyl.   82. The compound of claim 81, which is acetoxymethyl-   78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -3-   acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   83. The compound according to claim 81, which is acetoxymethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -3-   acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate. 84. The compound according to claim 77, wherein R4 represents 1-acetoxyethyl.   85. The compound according to claim 84, which is 1-acetoxy-   ethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   3-acétoxyprop-l-en-1-yl] -3-cephem-4-carboxylate.   86. The compound according to claim 84, which is 1-acetoxy-   ethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate. 87. The compound according to claim 77, wherein R4 represents pivaloyloxymethyl.   88. The compound according to claim 87, which is pivaloyloxy   methyl-7R - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(Z) -   3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   89. The compound according to claim 87, which is pivaloyloxy   methyl-76 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -3 - [(E) -   3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   90. The compound of claim 2 wherein R2 is acetyl. 91. The compound according to claim 90, wherein R3 represents a hydrogen atom.   92. The compound of claim 91, wherein R4 represents a hydrogen atom.   93. The compound according to claim 92, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -prop-1-ene l-yl] -3-cephem-4-carboxylic acid.   94. The compound of claim 92 which is 7C - [(Z) -   2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -prop-1-ene-1-yl] -3-cephem-4-carboxylic acid. The compound of claim 91, wherein R4 is acetoxymethyl.   96. The compound of claim 95, which is acetoxymethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -prop   1-ene-1-yl] -3-cephem-4-carboxylate.   97. The compound of claim 95, which is acetoxymethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -prop   1-ene-1-yl] -3-cephem-4-carboxylate. 98. The compound of claim 91, wherein R4 is 1-acetoxyethyl.   99. The compound of claim 98, which is 1-acetoxyethyl-   7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -prop   1-ene-1-yl] -3-cephem-4-carboxylate.   The compound of claim 98 which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -prop   1-ene-1-yl] -3-cephem-4-carboxylate. 101. The compound of claim 91, wherein R4 represents pivaloyloxymethyl.   102. The compound according to claim 101, which is pivaloyloxy   methyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate.   103. The compound according to claim 101, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -   prop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 91, wherein R4 is   5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl.   The compound of claim 104, which is 5-methyl-2-   oxo-1,3-dioxolen-4-ylmethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxy   imino) acetamido] -3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 104, which is 5-methyl-2-   oxo-1,3-dioxolen-4-ylmethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxy   imino) acetamido] -3 - [(E) -prop-1-ene-1-yl] -3-cephem-4-carboxylate. The compound of claim 90, wherein R3 is acetoxy. The compound of claim 107, wherein R4 is a hydrogen atom.   109. The compound according to claim 108, which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -3-acétoxyprop-   1-ene-1-yl] -3-cephem-4-carboxylic acid.   110. The compound of claim 108 which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -3-acétoxyprop-   1-ene-1-yl] -3-cephem-4-carboxylic acid.   The compound of claim 107 wherein R4 is acetoxymethyl.   112. The compound according to claim 111, which is acetoxymethyl   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -3- acetoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   113. The compound of claim 111 which is acetoxymethyl   7S - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -3-   acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate. The compound of claim 107, wherein R4 represents 1-acetoxyethyl.   The compound of claim 114, which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -3acétoxy-   prop-l-ene-l-yl] -3-cephem-4-carboxylate.   116. The compound of claim 114, which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -3-   acétoxyprop-l-ene-l-yl] -3-cephem-4-carboxylate. The compound of claim 107, wherein R4 is pivaloyloxymethyl.   118. The compound according to claim 117, which is pivaloyloxy   methyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(Z) -   3-acétoxyprop-1-ene-1-yl] -3-cephem-4-carboxylate.   119. The compound of claim 117 which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -   3-acétoxyprop-1-ene-1-yl] -3-cephem-4-carboxylate. 120. The compound according to claim 107, wherein R4 represents   5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl. '83757   The compound of claim 120, which is 5-methyl-2-   oxo-1,3-dioxolen-4-ylmethyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxy   imino) acetamido] -3 - [(Z) -3-acétoxyprop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 120, which is 5-methyl-2-   oxo-1,3-dioxolen-4-ylmethyl-78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (acetoxyimino) acetamido] -3 - [(E) -3-acétoxyprop- 1-ene-1-yl] -3-cephem-4-carboxylate. 123. The compound of claim 2 wherein R2 is isopropyl. The compound of claim 123, wherein R3 represents a hydrogen atom.   125. The compound of claim 124, wherein R4 is a hydrogen atom. -   The compound of claim 125, which is 7e - [(Z) -   2- (2-aminothiazol-4-yl) -2- (isopropyloxyimino) acetamido] -3 - [(Z) -prop-l-ene 1-yl] -3-cephem-4-carboxylic acid.   The compound of claim 124, wherein R4 is 1-acetoxyethyl.   128. The compound of claim 125, which is 1-acetoxyethyl-   7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (isopropyloxyimino) acetamido] -3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 124, wherein R4 represents pivaloyloxymethyl.   130. The compound according to claim 129, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (isopropyloxyimino) acetamido] -   3 - [(Z) -prop-l-ene-l-yl] -3-cephem-4-carboxylate.   The compound of claim 2 wherein R2 is allyl. 132. The compound according to claim 131, wherein R3 represents a hydrogen atom.   133. The compound of claim 132, wherein R represents a hydrogen atom.   134. The compound according to claim 133, which is 76 - [(Z) -   2- (2-aminothiazol-4-yl) -2- (allyloxyimino) acetamido] -3 - [(Z) -prop-1-ene   1-yl] -3-cephem-4-carboxylic acid. 135. The compound of claim 132, wherein R4 is 1-acetoxyethyl.   136. The compound of claim 135, which is 1-acetoxyethyl-   78 - [(Z) -2- (2-aminothiazol-4-yl) -2- (allyloxyimino) acetamido] -3 - [(Z) -prop   1-en-l-yl] -3-cephem-4-carboxylate. 137. The compound of claim 132, wherein R4 is pivaloyloxymethyl.   138. The compound according to claim 137, which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (allyloxyimino) acetamido] -3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate. The compound of claim 2, wherein R2 is ethyl.   140. The compound according to claim 139, a hydrogen atom.   The compound of claim 140, a hydrogen atom.   142. The compound of claim 141, 2- (2-aminothiazol-4-yl) -2 (ethoxyimino) acetamido 3-cephem-4-carboxylic acid. The compound of claim 140, 1-acetoxyethyl.   The compound of claim 143, wherein R3 is wherein R4 is which is the acid 7e - [(Z) - ] -3 - [(Z) -prop-l-ene-l-yl] - in which R4 represents which is 1-acetoxyethyl-   7B-C (Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3 - [(Z) -prop   1-ene-1-yl] -3-cephem-4-carboxylate. The compound of claim 140, wherein R4 is pivaloyloxymethyl.   146. The compound according to claim 145 which is pivaloyloxy   methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxyimino) acetamido] -3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate. The compound of claim 2 wherein R2 is cyclopropylmethyl. The compound of claim 147, wherein R 3 represents a hydrogen atom.   The compound of claim 148, wherein R4 is a hydrogen atom.   150. The compound of claim 149 which is 78 - [(Z) -   2- (2-aminothiazol-4-yl) -2- (cyclopropylméthoxyimino) acetamido] -3 - [(Z) -prop   1-ene-1-yl] -3-cephem-4-carboxylic acid. The compound of claim 148 wherein R4 is 1-acetoxyethyl.   152. The compound of claim 151, which is 1-acetoxyethyl-   7a - [(Z) -2- (2-aminothiazol-4-yl) -2- (cyclopropylméthoxyimino) acêtamido3-   3 - [(Z) -prop-l-ene-l-yl] -3-cephem-4-carboxylate. The compound of claim 148, wherein R4 is pivaloyloxymethyl.   The compound of claim 153, which is pivaloyloxy-   m'thyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (cyclopropylméthoxyimino) -   acetamido] -3 - [(Z) -prop-l-ene-l-yl] -3-ciphem-4-carboxylate. The compound of claim 2 wherein R2 is propargyl. The compound of claim 155 wherein R3 is a hydrogen atom. The compound of claim 156, wherein R4 is a hydrogen atom.   The compound of claim 157 which is 7B - [(Z) -   2- (2-aminothiazol-4-yl) -? - (propargyloxyimino) acetamido] -3 - [(Z) -prop-l-ene 1-YLJ-3-cephem-4-carboxylic acid.   The compound of claim 156, wherein R4 is 1-acetoxyethyl.   160. The compound of claim 159, which is 1-acetoxyethyl-   7B-r (Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxyimino) acetamido-3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate.   The compound of claim 156, wherein R represents pivaloyloxymethyl.   162. The compound of claim 161 which is pivaloyloxy   methyl-7B - [(Z) -2- (2-aminothiazol-4-yl) -2- (propargyloxyimino) acetamido] -   3 - [(Z) -prop-l-en-1-yl] -3-cephem-4-carboxylate.   163. An antibacterial pharmaceutical composition comprising an effective amount of a compound according to claim 2, in association with a pharmaceutically acceptable substantially non-toxic carrier or excipient. 164. A process for the preparation of the compound according to claim 1, which comprises reacting a compound of formula XV R5 TO $ l XV o '= 2h OR4 COOR ' 87 2583757   in which R5 represents a group of formula: O CE_ XVI or a group of formula: CCONH- 51.0I-I OR2 XVII R -NE H? 2   wherein: R1 represents a conventional blocking group used in cephalosporin chemistry for amino groups; R2a represents a classical blocking group used in the chemistry of   cephalosporin for hydroxy groups, an alkyl radical containing   1 to 4 carbon atoms, alkenyl or alkynyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or alkanoyl of 2 to 4 carbon atoms; and R4 represents a conventional blocking group used in cephalosporin chemistry for carboxylic groups, with an aldehyde of formula: R3CH2CHO   wherein: R3 has the same meanings as in claim 1,   in an inert organic reaction medium such as, for example, dichloromethane   methane, N, N'-dimethylformamide, isopropanol or a mixture thereof, optionally in the presence of lithium chloride, lithium bromide or lithium iodide at a reaction temperature of between 0 ° C. and 25 ° C., to prepare a compound of formula : ## STR1 ## C: = C: Cw2g O COOR 4 ' 2E RX 7E7 88 -. v -, -   and when R is benzylidaneamino (XVI), selectively removing this group and, if desired, converting the 3- (Z) isomer to the 3- (3-isomeric) by photochemical reaction and introducing the formula XVII for preparing a compound of formula: ## STR2 ## I CCO ORN   -K5) OR Na and then remove the blocking groups R1, R2a and R4 and, if desired, separating the 3- (Z) and 3- (E) isomers to prepare the compound of the formula: \ oR2 I Sa1 COOE   in which R2 and R3 have the same meaning as in the claim   1, and if desired, reacting the alkali metal salt or the ammonium salt of the compound Ia with the halide of the formula R 4b-x wherein X represents a halogen atom such as, for example, chlorine bromine or iodine; and   R4b represents a pivaloyloxymethyl, 1-acetoxyethyl, acetoxy-   methyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl or a group of formula: 0, \ 0 0 R1NuH2C- D <-C-OCE 2-   wherein R6 represents a hydrogen atom or a protecting group   conventional method used in cephalosporin chemistry for amino groups, 89 2583757   and, if desired, removing the protecting group to prepare the ester of formula: N C -ONE S h 3 Ib E N1 1N 2o N z HCC 2 s, ': 2o COOR -   in which R4 has the same meaning as in the 1.   The compound of claim 4 wherein R4 is (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.   166. The compound according to claim 165, (5-methyl-2-oxo-1,3-   dioxolen-4-yl) methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) -   acetamido] -3 - [(Z) -prop-1-en-1-yl] -3-cephem-4-carboxylate. The compound of claim 4, wherein R4 represents the 1- (ethoxycarbonyloxy) ethyl.   168.- The compound of claim 165, 1- (ethoxycarbonyloxy) -   ethyl-7o - [(Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido] -3 - [(Z) -   prop-1-en-1-yl] -3-cephem-4-carboxylate.